Patent Publication Number: US-2003236630-A1

Title: Classification of polypeptides by ligand geometry and related methods

Description:
BACKGROUND OF THE INVENTION  
       [0001] The present invention relates generally to interactions between ligands and polypeptides and more specifically to determining structure-related properties of a ligand when bound to different polypeptides.  
       [0002] Structure determination plays a central role in chemistry and biology due to the correlation between the structure of a molecule and its function. Although a full understanding of this correlation is not yet established, one can gain insight into the function of a molecule from its deduced structure. Thus, the structure can provide a strong basis for formulating experiments to determine function. Conversely, the eventual disclosure of a structure for a well studied molecule can have a significant effect in converging apparently disparate observations of function into a consistent description of the molecule&#39;s activity.  
       [0003] Practical applications which are becoming increasingly dependent upon structure information include, for example, the production of therapeutic drugs. Therapeutic drugs can be designed by synthesizing a molecule that mimics a ligand known to interact with a target receptor. Alternatively, a therapeutic drug can be designed by computer assisted methods in which a molecule is designed to dock to a binding site on a receptor of known structure. By structure-based methods such as these, lead compounds can be identified for further development.  
       [0004] Using a similar structure based approach a receptor can be engineered to yield improved or novel functions. For example, changes can be made at a ligand binding site in a polypeptide receptor based on the known structure of the receptor. Given that a polypeptide receptor can contain hundreds or even thousands of amino acid residues, of which only a few may contact a ligand, structural information is useful in identifying where changes should be made in the polypeptide to alter ligand binding. Polypeptide receptors engineered as such can be used for a variety of practical applications including, for example, industrial catalysis, therapeutics, and bioremediation.  
       [0005] Although methods for structure determination are evolving, it is currently difficult, costly and time consuming to determine the structure of a polypeptide or ligand. It can often be even more difficult to produce a polypeptide-ligand complex in a condition allowing determination of a structure for the bound complex. Resorting to determining a structure for the receptor individually can have limited value, particularly if the location of ligand binding is difficult to identify due to the large size of most polypeptide receptors. Similarly, determination of a structure of an unbound ligand can have limited usefulness because an unbound ligand has multiple conformations and the most stable conformation of an unbound ligand is often different from its conformation when bound to a receptor.  
       [0006] Theoretical modeling of ligand-polypeptide interactions is one alternative that has been attempted in cases where the structure of the polypeptide-ligand complex is not available. In this approach a ligand is fitted to a structure of a polypeptide. The polypeptide structure used can be determined empirically or theoretically. Theoretical determination of a hypothetical molecular structure for a polypeptide by ab initio methods is a relatively undeveloped method. Another theoretical approach, referred to as homology modeling, has been used to infer structure based on comparison with molecules of known structure.  
       [0007] The successful application of homology modeling to determining polypeptide-ligand interactions relies upon choosing a correct polypeptide template for comparison. In most cases criteria for comparison are unavailable or unreliable. For example, it is common to produce a hypothetical structure of a target polypeptide based on the empirically determined structure of a template polypeptide having similar sequence. However, similarities in sequence do not always yield similar structures and conversely, similar structures have been observed for two polypeptides having significantly diverged sequences.  
       [0008] Thus, there exists a need for efficient methods to identify properties of a ligand that confer binding specificity for polypeptide receptors. A need also exists for methods to classify polypeptides and ligands according to structural characteristics. The present invention satisfies this need and provides related advantages as well.  
       SUMMARY OF THE INVENTION  
       [0009] The invention provides a method for identifying a pharmacocluster. The method includes the steps of (a) determining bound conformations of a ligand bound to different polypeptides, and (b) clustering two or more bound conformations of the ligand having substantially the same bound conformation, thereby identifying a pharmacocluster. The invention also provides a method for identifying a member of a pharmacocluster. The invention also provides a method for identifying a polypeptide pharmacofamily. The method includes the steps of (a) determining bound conformations of a ligand bound to different polypeptides of a polypeptide family, and (b) identifying two or more bound conformations of the ligand having substantially different bound conformations, thereby identifying at least two polypeptide pharmacofamilies exhibiting binding specificity for the two or more substantially different bound conformations of the ligand. 
     
    
    
     BRIEF DESCRIPTION OF THE DRAWINGS  
     [0010]FIG. 1 shows pharmacoclusters identified from a database of 156 bound structures of nicotinamide adenine dinucleotide or nicotinamide adenine dinucleotide phosphate. Structures were generated using the overlay function in INSIGHT98 (Molecular Simulations Inc., San Diego, Calif.).  
     [0011]FIG. 2 shows the nomenclature used herein for atom names in the NAD(P) molecule.  
     [0012]FIG. 3 shows conformer models with interacting atoms from bound polypeptide and ordered waters overlayed. Models in parts A through H were derived from pharmacoclusters 1-8, respectively as described in the Examples. Overlayed atoms and waters are identified as either hydrogen bond donors (donors), hydrogen bond acceptors (acceptors), sulfurs (sulfurs), waters (waters), or atoms that can be hydrogen bond acceptors or hydrogen bond donors (acceptors/donors) according to the legends under each conformer model.  
     [0013]FIG. 4 shows a portion of a 2D [ 1 H, 1 H] NOESY spectrum recorded with a 0.2 ml sample of 1 mM NADP and 200 μM of enzyme 1-deoxy D-xylulose 5-phosphate reductoisomerase (DOXP). Atoms are identified according to FIG. 2. Spectra are reported as parts per million (ppm). Since the ligand is in fast exchange and is in excess over polypeptide, cross peaks represent transferred NOEs.  
     [0014]FIG. 5 shows high affinity binding of compound TTE0001.001.A07 to polypeptide enzymes of pharmacofamily 1 (panel A) and pharmacofamily 8 (panel B). Double reciprocal plots of reaction rate versus concentration of NADH (panel A) or NADPH (panel B) are shown for each enzyme in the presence of various concentrations of compound TTE0001.001.A07. Concentrations of compound TTE0001.001.A07 shown to the right of the plot A correspond 7.1 μM (open triangles), 3.6 μM (closed triangles), 1.8 μM (open circles) and no added compound (closed circles). Concentrations of compound TTE0001.001.A07 shown to the right of the plot B correspond 56.2 μM (open triangles), 37.5 μM (closed triangles), 18.7 μM (open circles) and no added compound (closed circles). Inhibitory dissociation constants (K is ) determined from the data are shown in the upper left corner of the respective plot.  
     [0015]FIG. 6 shows high affinity binding of compound TTE0001.002.D02 to a polypeptide enzyme of pharmacofamily 1. A double reciprocal plot of reaction rate versus concentration of NADH is shown for the enzyme in the presence of various concentrations of compound TTE0001.002.D02. Concentrations of compound TTE0001.002.D02 shown to the right of the plot A correspond 20.6 μM (open triangles), 13.7 μM (closed triangles), 6.9 μM (open circles) and no added compound (closed circles). An inhibitory dissociation constant (K is ) determined from the data is shown in the upper left corner of the plot.  
     [0016]FIG. 7 shows a pharmacophore model derived from the coordinates presented in Table 3 for pharmacofamily 1. FIG. 7A shows a feature of the pharmacophore model including a volume defining the shape of conformer model 1 which is indicated by grey spheres and superimposed on the conformer model having coordinates listed in Table 3C. FIG. 7B shows three features of the pharmacophore model including a hydrophobic region of the nicotinamide ring, a hydrogen bond acceptor positioned at the averaged coordinates for the location of 17 hydrogen bond acceptors in the polypeptides of pharmacofamily 1, and a hydrogen bond donor positioned where a hydrogen bond donor of a ligand would be expected to have favorable interactions with hydrogen bond acceptors observed in 11 of the 17 polypeptides in pharmacofamily 1. FIG. 7C shows a combination of features of FIGS. 7A and 7B present in a pharmacophore model and superimposed on the conformer model. 
    
    
     DETAILED DESCRIPTION OF THE INVENTION  
     [0017] The invention provides pharmacoclusters and methods for identifying a pharmacocluster from bound conformations of a ligand bound to different polypeptides. The methods are applicable for identifying a conformation-dependent property of a ligand based on bound conformations of the ligand in a pharmacocluster. The methods are also applicable for classifying polypeptides, from a family of polypeptides that bind the same ligand, into pharmacofamilies based on bound conformations of the ligand. Accordingly, methods are provided for grouping polypeptides into pharmacofamilies by determining bound conformations of a ligand or a conformation-dependent property of a ligand independent of a determination of the structure of the polypeptide. An advantage of classifying polypeptides according to bound conformations of a ligand is that a pharmacofamily is likely to contain polypeptides having greater binding specificity for a particular molecule than other polypeptides in the same family. Thus, the methods allow identification of a pharmacofamily that can specifically interact with a particular therapeutic agent or drug.  
     [0018] Additionally, the methods of the invention can be used to determine a conformer model or pharmacophore model based on a bound conformation or conformation-dependent property of a ligand bound to polypeptides in a pharmacofamily. The invention is therefore advantageous in providing a model for the design and identification of therapeutic compounds having specificity for a pharmacofamily of polypeptides.  
     [0019] Another advantage of the invention is that the methods provide a correlation between ligand conformation, a parameter that is relatively easy to measure, and polypeptide structure, a parameter of tremendous value but often difficult to measure. Therefore, the methods of the invention can be used to determine structural characteristics of a polypeptide based on a conformation-dependent property of a bound ligand.  
     [0020] As used herein, the term “pharmacocluster” refers to a collection of substantially the same bound conformations of a ligand, or portion thereof, bound to two or more polypeptides. A member conformation of a pharmacocluster can have (1) a conformation that is more similar to an average conformation of the members in its pharmacocluster than to any other pharmacocluster and (2) a conformation that is more similar to an average conformation of the members in its own pharmacocluster than the most similar average structures from different pharmacoclusters are to each other, wherein the pharmacoclusters consist of conformations of the same ligand or portion thereof. The pharmacocluster is determined for a ligand bound to different polypeptides but does not require that a structure of the polypeptide be known or included as part of a bound conformation of a ligand. A bound conformation of a ligand can include the entire ligand structure or selected atoms including a portion of the complete atomic composition of the ligand so long as the number of atoms provides sufficient information to distinguish one pharmacocluster from another. A pharmacocluster can include both the bound conformations of a ligand, or portion thereof, and one or more atoms that both interact with the ligand and are from a bound polypeptide. Thus, a pharmacocluster can include conformational information of 1 or more, 2 or more, 5 or more, 10 or more, 20 or more, 30 or more, 40 or more, 50 or more or 100 or more atoms of a ligand bound conformation.  
     [0021] Accordingly, portions of bound conformations of two or more different ligands can be included in a ligand pharmacocluster so long as the portions selected from each ligand have a core bound conformation that is substantially the same. A core bound conformation can consist of portions of bound conformations of ligands wherein the portions have identical structural formula and conformation. A core bound conformation can also consist of portions of bound conformations of ligands wherein the portions have different structural formulas so long as the portions have substantially the same conformation. The structural formula, as it is understood in the art, is a 2 dimensional representation of a molecule that identifies the atoms and covalent bonds between each atom in the molecule. The structural formula does not necessarily include information sufficient to determine conformation of a molecule. For example, a common structural formula representation of cyclohexane can be a hexagon with 2 hydrogens attached to each carbon being in equivalent positions. However, a stable conformation of cyclohexane in solution may appear as a “chair” or “boat” shape with hydrogens in either axial or equitorial positions relative to the molecular plane.  
     [0022] As used herein, the term “conformation-dependent property,” when used in reference to a ligand, refers to a characteristic of a ligand that specifically correlates with the three dimensional structure of a ligand or the orientation in space of selected atoms and bonds of the ligand. Thus, a ligand bound to a polypeptide in a distinct conformation will have at least one unique conformation-dependent property correlated with the bound conformation of the ligand. A conformation-dependent property can be derived from or include the entire ligand structure or selected atoms and bonds, including a fragment or portion of the complete atomic composition of the ligand. A conformation-dependent property that includes selected atoms and bonds of a ligand can include 2 or more, 3 or more, 5 or more, 10 or more, 15 or more, 20 or more, 25 or more, or 50 or more atoms of a bound conformation of a ligand.  
     [0023] A characteristic that specifically correlates with a three dimensional structure of a ligand is a characteristic that is substantially different between at least two different bound conformations of the same ligand and, therefore, distinguishes the two different bound conformations. A conformation-dependent property can include a physical or chemical characteristic of a ligand, for example, absorption and emission of heat, absorption and emission of electromagnetic radiation, rotation of polarized light, magnetic moment, spin state of electrons, or polarity. A conformation-dependent property can also include a structural characteristic of a ligand based, for example, on an X-ray diffraction pattern or a nuclear magnetic resonance (NMR) spectrum. A conformation-dependent property can additionally include a characteristic based on a structural model, for example, an electron density map, atomic coordinates, or x-ray structure. A conformation-dependent property can include a characteristic spectroscopic signal based on, for example, Raman, circular dichroism (CD), optical rotation, electron paramagnetic resonance (EPR), infrared (IR), ultraviolet/visible absorbance (UV/Vis), fluorescence, or luminescence spectroscopies. A conformation-dependent property can also include a characteristic NMR signal, for example, chemical shift, J coupling, dipolar coupling, cross-correlation, nuclear spin relaxation, transferred nuclear Overhauser effect, or combinations thereof. A conformation-dependent property can additionally include a thermodynamic or kinetic characteristic based on, for example, calorimetric measurement or binding affinity measurement. Furthermore, a conformation-dependent property can include characteristic based on electrical measurement, for example, voltammetry or conductance.  
     [0024] As used herein, “selected” conformation-dependent properties are identified to form a set of conformation-dependent properties that can include, for example, the entire set of conformation-dependent properties associated with the bound conformations of a ligand in a pharmacocluster or a subset of conformation-dependent properties associated with the bound conformations of a ligand in a pharmacocluster, so long as the subset of conformation-dependent properties are sufficient to identify a unique conformation of the ligand. A selected conformation-dependent property can include any of the above described properties, for example, a physical or chemical property, structural data, a structural model, a spectroscopic signal, a thermodynamic or kinetic measurement or an electrical measurement.  
     [0025] As used herein, the term “bound conformation,” when used in reference to a ligand, refers to the location of atoms of a ligand relative to each other in three dimensional space, where the ligand is bound to a polypeptide. The location of atoms in a ligand can be described, for example, according to bond angles, bond distances, relative locations of electron density, probable occupancy of atoms at points in space relative to each other, probable occupancy of electrons at points in space relative to each other or combinations thereof.  
     [0026] As used herein, a “selected” bound conformation refers to a set of bound conformations that can include, for example, the entire set of defined bound conformations or a subset of bound conformations of a ligand.  
     [0027] As used herein, the term “clustering” refers to assigning related bound conformations of a ligand, or portion thereof, into a first collection such that the conformations residing in the first collection can be overlaid with substantial overlap and bound conformations from two different collections cannot be overlaid with a better overlap than that resulting from members of the first collection. Exemplary clustering of ligand conformations are disclosed herein (see Example I).  
     [0028] As used herein, the term “ligand” refers to a molecule that can specifically bind to a polypeptide. Specific binding, as it is used herein, refers to binding that is detectable over non-specific interactions by quantifiable assays well known in the art. A ligand can be essentially any type of natural or synthetic molecule including, for example, a polypeptide, nucleic acid, carbohydrate, lipid, amino acid, nucleotide or any organic derived compound. The term also encompasses a cofactor or a substrate of a polypeptide having enzymatic activity, or substrate that is inert to catalytic conversion by the bound polypeptide. Specific binding to a polypeptide can be due to covalent or non covalent interactions.  
     [0029] As used herein, the term “bound to two or more polypeptides,” when used in reference to a ligand is intended to refer to two or more complexes consisting of a ligand and a polypeptide. A complex can include, for example, a single ligand bound to a single polypeptide. A complex can also include a single ligand bound to more than one polypeptides including, for example, a complex in which a ligand is bound at the interface of interacting polypeptides. A complex can also include multiple ligands, however, conformation dependent properties of all ligands of the complex need not be identified. A complex results from a specific interaction between a polypeptide and a ligand.  
     [0030] As used herein, the term “substantially the same,” when used in reference to bound conformations of a ligand, or portion thereof, is intended to refer to two or more bound conformations that can be overlaid upon each other in 3 dimensional space such that all corresponding atoms between the two conformations are overlapped. Accordingly, “substantially different” bound conformations cannot be overlaid upon each other in 3-dimensional space such that all corresponding atoms between the two bound conformations are overlapped.  
     [0031] As used herein, the term “polypeptide” is intended to refer to a peptide polymer of two or more amino acids. The term is similarly intended to include polymers containing amino acid sterioisomers, analogues and functional mimetics thereof. For example, derivatives can include chemical modifications of amino acids such as alkylation, acylation, carbamylation, iodination, or any modification which derivatizes the polypeptide. Analogues can include modified amino acids, for example, hydroxyproline or carboxyglutamate, and can include amino acids, or analogs thereof, that are not linked by peptide bonds. Mimetics encompass chemicals containing chemical moieties that mimic the function of the polypeptide regardless of the predicted three-dimensional structure of the compound. For example, if a polypeptide contains two charged chemical moieties in a functional domain, a mimetic places two charged chemical moieties in a spatial orientation and constrained structure so that the corresponding charge is maintained in three-dimensional space. Thus, all of these modifications are included within the term “polypeptide” so long as the polypeptide retains its binding function.  
     [0032] As used herein, the term “root mean square deviation,” or RMSD, refers to a standard deviation which quantifies the structural variability in a population of bound conformations of a ligand. The term is intended to be consistent with its meaning as understood in the art as described for example in Doucet and Weber,  Computer - Aided Molecular Design: Theory and Applications,  Academic Press, San Diego Calif. (1996).  
     [0033] As used herein, the term “family,” when used in reference to characterizing polypeptides having ligand binding activity, is intended to refer to polypeptides that can bind to the same ligand, or portion thereof. A polypeptide family can contain polypeptides having binding activity for a common ligand with sufficient affinity, avidity or specificity to allow measurement of the binding event. As defined herein a “member” of a polypeptide family refers to an individual polypeptide that can be classified in a polypeptide family because the polypeptide binds a ligand, or portion thereof, that binds another polypeptide in a polypeptide family. The bound conformations of a ligand bound by individual members of a family can be substantially the same or different from each other.  
     [0034] As used herein, the term “pharmacofamily,” when used in reference to polypeptides, is intended to refer to polypeptides that can be classified together in a population because they individually bind a ligand such that the ligand is bound in substantially the same conformation. As defined herein a “member” of a polypeptide pharmacofamily refers to an individual polypeptide that is classified in a polypeptide pharmacofamily because the polypeptide binds a conformation of a ligand that is substantially the same as a conformation of the ligand bound to another polypeptide in the pharmacofamily.  
     [0035] As used herein, the term “grouping” refers to assigning related polypeptides into a family or pharmacofamily such that the polypeptide members of a family bind the same ligand and the polypeptide members of a pharmacofamily bind substantially the same bound conformation of a ligand.  
     [0036] As used herein, the term “fold,” when used in reference to a polypeptide, refers to a specific geometric arrangement and connectivity of a combination of secondary structure elements in a polypeptide structure. Secondary structure elements of a polypeptide that can be arranged into a fold including, for example, alpha helices, beta sheets, turns and loops are well known in the art. Folds of a polypeptide can be recognized by one skilled in the art and are described in, for example, Branden and Tooze,  Introduction to protein structure,  Garland Publishing, New York (1991) and Richardson,  Adv. Prot. Chem.  34:167-339 (1981).  
     [0037] As used herein, “modeling the three dimensional structure” when used in reference to a polypeptide refers to determining a conformation for a polypeptide. A conformation of a polypeptide can be determined, for example, from empirical data specifying structure or from a compared conformation used as a template. A conformation can be determined at any desired level of resolution sufficient to identify, for example, overall shape of a polypeptide, tertiary structure elements, secondary structure elements, polypeptide backbone structure, amino acid residue identity or location of individual atoms.  
     [0038] As used herein, the term “structural model,” when used in reference to a polypeptide, refers to a representation of a 3 dimensional structure of a polypeptide. A structural model can be determined from empirical data derived from, for example, X-ray crystallography or nuclear magnetic resonance spectroscopy. A structural model can also be derived from a theoretical calculation including, for example, comparison to a known structure or ab initio molecular modeling. A representation of a structural model can include, for example, an electron density map, atomic coordinates, x-ray structure model, ball and stick model, density map, space filling model, surface map, Connolly surface, Van der Waals surface or CPK model.  
     [0039] As used herein, the term “conformer model” refers to a representation of points in a defined coordinate system wherein a point corresponds to a position of an atom in a bound conformation of a ligand. The coordinate system is preferably in 3 dimensions, however, manipulation or computation of a model can be performed in 2 dimensions or even 4 or more dimensions in cases where such methods are preferred. A point in the representation of points can, for example, correlate with the center of an atom. Additionally, a point in the representation of points can be incorporated into a line, plane or sphere to include a shape of one or more atom or volume occupied by one or more atom. A conformer model can be derived from 2 or more bound conformations of a ligand. For example a conformer model can be generated from 3 or more, 4 or more, 5 or more, 6 or more, 7 or more, 8 or more, 10 or more, 15 or more, 20 or more or 25 or more bound conformations of a ligand.  
     [0040] As used herein, the term “average structure,” when used in reference to bound conformations of a ligand in a pharmacocluster, refers to conformer model, derived by superimposing the bound conformations of a ligand in a pharmacocluster, and determining an average location in space for corresponding atoms.  
     [0041] As used herein, the term “pharmacophore model” refers to a representation of points in a defined coordinate system wherein a point corresponds to a position or other characteristic of an atom or chemical moiety in a bound conformation of a ligand and/or an interacting polypeptide or ordered water. An ordered water is an observable water in a model derived from structural determination of a polypeptide. A pharmacophore model can include, for example, atoms of a bound conformation of a ligand, or portion thereof. A pharmacophore model can include both the bound conformations of a ligand, or portion thereof, and one or more atoms that both interact with the ligand and are from a bound polypeptide. Thus, in addition to geometric characteristics of a bound conformation of a ligand, a pharmacophore model can indicate other characteristics including, for example, charge or hydrophobicity of an atom or chemical moiety. A pharmacaphore model can incorporate internal interactions within the bound conformation of a ligand or interactions between a bound conformation of a ligand and a polypeptide or other receptor including, for example, van der Waals interactions, hydrogen bonds, ionic bonds, and hydrophobic interactions. A pharmacophore model can be derived from 2 or more bound conformations of a ligand. For example a conformer model can be generated from 3 or more, 4 or more, 5 or more, 6 or more, 7 or more, 8 or more, 10 or more, 15 or more, 20 or more or 25 or more bound conformations of a ligand.  
     [0042] A point in a pharmacophore model can, for example, correlate with the center of an atom or moiety. Additionally, a point in the representation of points can be incorporated into a line, plane or sphere to indicate a characteristic other than a center of an atom or moiety including, for example, shape of an atom or moiety or volume occupied by an atom or moiety. The coordinate system of a pharmacophore model is preferably in 3 dimensions, however, manipulation or computation of a model can be performed in 2 dimensions or even 4 or more dimensions in cases where such methods are preferred. Multidimensional coordinate systems in which a pharmacophore model can be represented include, for example, Cartesian coordinate systems, fractional coordinate systems, or reciprocal space. The term pharmacophore model is intended to encompass a conformer model.  
     [0043] As used herein, the term “moiety” refers to a group of atoms that form a part or portion of a larger molecule. A moiety can consist of any number of atoms in a portion of a ligand and can correlate with a physical or chemical property conferred upon the ligand by the combined atoms. Exemplary moieties of a nicotinamide adenine dinucleotide ligand include a phosphate, nicotinamide ring, amino group, amide group or ribose ring. In addition, a nicotinamide adenine dinucleotide group can be a moiety. For example, a nicotinamide adenine dinucleotide can be a moiety of the 2′P phosphate in a nicotinamide adenine dinucleotide phosphate molecule (see FIG. 2 for location of the 2′P phosphate in nicotinamide adenine dinucleotide phosphate).  
     [0044] The invention provides a method for identifying a pharmacocluster. The method includes the steps of (a) determining bound conformations of a ligand bound to different polypeptides, and (b) clustering two or more bound conformations of the ligand having substantially the same bound conformation, thereby identifying a pharmacocluster. The invention also provides a method for identifying a member of a pharmacocluster. The method includes the steps of (a) determining a bound conformation of a ligand bound to a polypeptide; and (b) determining a pharmacocluster having substantially the same bound conformation as the bound conformation, thereby identifying the bound conformation of the ligand as a member of the pharmacocluster.  
     [0045] A bound conformation of a ligand bound to a polypeptide can be determined from a previously observed molecular structure or from data specifying a molecular structure for a bound conformation of a ligand. Previously observed structures can be acquired for use in the invention by searching a database of existing structures. An example of a database that includes structures of bound conformations of ligands bound to polypeptides is the Protein Data Bank (PDB, operated by the Research Collaboratory for Structural Bioinformatics, see Berman et al.,  Nucleic Acids Research,  28:235-242 (2000)). A database can be searched, for example, by querying based on chemical property information or on structural information. In the latter approach, an algorithm based on finding a match to a template can be used as described, for example, in Martin, “Database Searching in Drug Design,”  J. Med. Chem.  35:2145-2154 (1992).  
     [0046] A bound conformation of a ligand bound to a polypeptide can be determined from an empirical measurement, or from a database. Data specifying a structure can be acquired using any method available in the art for structural determination of a ligand bound to a polypeptide. For example, X-ray crystallography can be performed with a crystallized complex of a polypeptide and ligand to determine a bound conformation of the ligand bound to the polypeptide. Methods for obtaining such crystal complexes and determining structures from them are well known in the art as described for example in McRee et al.,  Practical Protein Crystallography,  Academic Press, San Diego 1993; Stout and Jensen,  X - ray Structure Determination: A practical guide,  2 nd  Ed. Wiley, New York (1989); and McPherson,  The Preparation and Analysis of Protein Crystals,  Wiley, New York (1982). Another method useful for determining a bound conformation of a ligand bound to a polypeptide is Nuclear Magnetic Resonance (NMR). NMR methods are well known in the art and include those described for example in Reid,  Protein NMR Techniques,  Humana Press, Totowa N.J. (1997); and Cavanaugh et al.,  Protein NMR Spectroscopy: Principles and Practice,  ch. 7, Academic Press, San Diego Calif. (1996).  
     [0047] A bound conformation of a ligand can also be determined from a hypothetical model. For example, a hypothetical model of a bound conformation of a ligand can be produced using an algorithm which docks a ligand to a polypeptide of known structure and fits the ligand to the polypeptide binding site. Algorithms available in the art for fitting a ligand structure to a polypeptide binding site include, for example, DOCK (Kuntz et al.,  J. Mol. Biol.  161:269-288 (1982)) and INSIGHT98 (Molecular Simulations Inc., San Diego, Calif.).  
     [0048] A molecular structure can be conveniently stored and manipulated using structural coordinates. Structural coordinates can occur in any format known in the art so long as the format can provide an accurate reproduction of the observed structure. For example, crystal coordinates can occur in a variety of file types including, for example, .fin, .df, .phs, or .pdb as described for example in McRee, supra. Although the examples above describe structural coordinates derived from X-ray crystallographic analysis or NMR spectroscopy, one skilled in the art will recognize that structural coordinates can be derived from any method known in the art to determine a bound conformation of a ligand bound to a polypeptide.  
     [0049] Structures at atomic level resolution can be useful in the methods of the invention. Resolution, when used to describe molecular structures, refers to the minimum distance that can be resolved in the observed structure. Thus, resolution where individual atoms can be resolved is referred to in the art as atomic resolution. Resolution is commonly reported as a numerical value in units of Angstroms (Å, 10 −10  meter) correlated with the minimum distance which can be resolved such that smaller values indicate higher resolution. Bound conformations of a ligand useful in the methods of the invention can have a resolution better than about 10 Å, 5 Å, 3 Å, 2.5 Å, 2.0 Å, 1.5 Å, 1.0 Å, 0.8 Å, 0.6 Å, 0.4 Å, or about 0.2 Å or better. Resolution can also be reported as an all atom RMSD as used, for example, in reporting NMR data. Bound conformations of a ligand useful in the methods of the invention can have an all atom RMSD better than about 10 Å, 5 Å, 3 Å, 2.5 Å, 2.0 Å, 1.5 Å, 1.0 Å, 0.8 Å, 0.6 Å, 0.4 Å, or about 0.2 Å or better.  
     [0050] An advantage of the methods of the invention is that a structure of a polypeptide bound to a bound conformation of a ligand need not be determined to identify a pharmacocluster. Thus, methods that detect only the structure of the ligand can be used in the invention. In some cases determination or refinement of only the structure of the ligand in a polypeptide-ligand complex will be required. In addition, methods that detect a conformation-dependent property of the ligand can be used to identify a pharmacocluster. Methods that can be used to determine a conformation-dependent property of a ligand in a polypeptide-ligand complex without determining the structure of the polypeptide include, for example, Electron Nuclear Double Resonance spectroscopy (ENDOR, as described in Van Doorslaer and Schweiger,  Naturwissenschaften  87:245-55(2000)), Electron Paramagnetic Resonance spectroscopy (EPR, described in Cantor and Schimmel  Biophysical Chemistry, Part I: The conformation of biological macromolecules  W. H. Freeman and Company (1980)), chemically induced dynamic nuclear polarization (CIDNP, described in Siebert et al.,  Glycoconj J.  14:945-9 (1997) and Consonni et al.,  FEBS Lett.  372:135-9 (1995)), solid state NMR (described in Mehring, M.  High Resolution NMR spectroscopy in Solids,  2 nd  ed. Springer-Verlag, Berlin (1983) and liquid phase NMR (described in Wüthrich,  NMR of Proteins and Nucleic Acids  John Wiley &amp; Sons, Inc. (1986)). Thus, the invention can be performed in a manner whereby the time and cost associated with a full determination of a polypeptide structure is avoided.  
     [0051] Any representation that correlates with the structure of a bound conformation of a ligand can be used in the methods of the invention. For example, a convenient and commonly used representation is a displayed image of the structure. Displayed images that are particularly useful for determining the bound conformation of a ligand bound to polypeptides include, for example, ball and stick models, density maps, space filling models, surface map, Connolly surfaces, Van der Waals surfaces or CPK model. Display of images as a computer output, for example, on a video screen can be advantageous as described below.  
     [0052] Clustering can be performed with any ligand or any number of bound conformations of a ligand. The methods of the invention can be performed by clustering 2 or more bound conformations of a ligand. For example, clustering can be performed with 3 or more, 4 or more, 5 or more, 6 or more, 7 or more, 8 or more, 9 or more, 10 or more, 11 or more, 12 or more, 13 or more, 14 or more, 15 or more or 20 or more bound conformations of a ligand. The methods of the invention can be used with any number bound conformations of a ligand. Due to the large sizes of data sets required to represent bound conformations of a ligand, methods of clustering bound conformations are generally performed on a computer. The methods are compatible with any computer that can support molecular modeling software including for example a personal computer, silicon graphics workstation, or supercomputer. A variety of computer software programs are available for molecular modeling including, for example, GRASP (Nicholls, A., supra), ALADDIN (Van Drie et al. supra), INSIGHT98 (Molecular Simulations Inc., San Diego Calif.), RASMOL (Sayle et al.,  Trends Biochem Sci.  20:374-376 (1995)) and MOLMOL (Koradi et al.,  J. Mol. Graphics  14:51-55 (1996)).  
     [0053] Once a bound conformation of a ligand bound to different polypeptides has been determined, two or more bound conformations of the ligand can be compared and those having substantially the same bound conformation can be clustered. Methods of comparison include, for example, a method that provides alignment of two or more bound conformations of a ligand and evaluation of the degree of overlap in the two structures. Methods of comparison can be performed in an iterative fashion until a best fit is identified.  
     [0054] Methods of comparing bound conformations of bound ligands include, for example, cluster analysis, visual inspection and pairwise structural comparisons. Cluster analysis is commonly performed by, but not limited to, partitioning methods or hierarchical methods as described, for example, in Kauffman and Rousseeuw,  Finding Groups in Data: An Introduction to Cluster Analysis,  John Wiley and Sons Inc., New York (1990). Partitioning methods that can be used include, for example, partitioning around mediods, clustering large applications, and fuzzy analysis, as described in Kauffman and Rousseeuw, supra. Hierarchical methods useful in the invention include, for example, agglomerative nesting, divisive analysis, and monothetic analysis, as described in Kauffman and Rousseeuw, supra. Algorithms for cluster analysis of molecular structures are known in the art and include, for example, COMPARE (Chiron Corp, 1995; distributed by Quantum Chemistry program Exchange, Indianapolis Ind.). COMPARE can be used to make all possible pairwise comparisons between a set of conformations of the same ligand(s). COMPARE reads PDB files and uses a Ferro-Hermanns ORIENT algorithm for a least squares root mean square (RMS) fit. The structures can be clustered into groups using the Jarvis-Patrick nearest neighbors algorithm. Based on the RMS deviation between ligand conformers, a list of ‘nearest neighbors’ for each conformer are generated. Two conformers are then grouped together or clustered if: (1) the RMS deviation is sufficiently small and (2) if both conformers share a determined number of common ‘neighbors’. Both criteria are adjusted by the program to generate clusters based on a user defined cutoff for distance between individual clusters. Follow up analysis was conducted using InsightII to verify clusters. A member conformation is identified as being closer to the averaged coordinates of conformations within its family than to the averaged coordinates of any other family.  
     [0055] Using methods such as those described above, one skilled in the art will know how to identify conformations that are substantially the same. For example, similarity can be evaluated according to the goodness of fit between two or more bound conformations of a ligand. Goodness of fit can be represented by a variety of parameters known in the art including, for example, the root mean square deviation (RMSD). A lower RMSD between structures correlates with a better fit compared to a higher RMSD between structures. Bound conformations of a ligand having substantially the same conformations can be identified by comparing mean RMSD values within and between pharmacoclusters. Accordingly, bound conformations of a ligand having substantially the same conformations can have a mean RMSD compared to an average structure for the pharmacocluster that is less than 1.1 Å. Two or more bound conformations of a ligand can be clustered by assigning bound conformations of a ligand into a collection such that the conformations of a ligand residing in the collection are substantially the same., Members of a pharmacocluster can also be identified as having RMSD values compared to an average structure for the pharmacocluster that are less than 1.0 Å, 0.9 Å, 0.8 Å, 0.7 Å, 0.6 Å, 0.5 Å, 0.4 Å, 0.3 Å, 0.2 Å or 0.1 Å.  
     [0056] A bound conformation of a ligand that is a member of a pharmacocluster can also be identified by comparing the RMSD for the bound conformation to an average conformation of the members in multiple pharmacoclusters. Using this value for comparison, a member conformation is identified as having a smaller RMSD when compared to the averaged coordinates of conformations within its family than when compared to the averaged coordinates of any other family. In addition, a member of a pharmacocluster can be identified as having an RMSD compared to an average conformation of the members in a pharmacocluster that is smaller than the RMSD between each family&#39;s average coordinates. For example, as described in Example I, RMSD values for members of pharmacoclusters 1-8 as presented in Tables 3A, 4A, 5A, 6A, 7A, 8A, 9A or 10A, respectively, can be compared to RMSD values between each pharmacocluster as presented in Table 2. Comparisons similar to those described above can be made for bound conformations of any ligand according to the methods described in the Examples.  
     [0057] In addition, bound conformations of a ligand can be compared with respect to dihedral angles at particular bonds. Exemplary methods for comparing dihedral angles between pharmacoclusters is described in Example I and Table 1. Comparison between dihedral angles can be used, for example, in combination with overall RMSD comparisons such as those described above. Therefore, bound conformations that are not easily distinguished by comparison of overall RMSD alone, can be distinguished according to the combined comparison of RMSD and dihedral angle. Bound conformations of a ligand that are members of different pharmacoclusters can have dihedral angles that differ, for example, by at least about 10 degrees, 30 degrees, 45 degrees, 90 degrees or 180 degrees.  
     [0058] The invention also provides a pharmacocluster selected from the cluster consisting of pharmacocluster 1, pharmacocluster 2, pharmacocluster 3, pharmacocluster 4, pharmacocluster 5, pharmacocluster 6, pharmacocluster 7, and pharmacocluster 8 correlated with the pharmacofamilies listed in Table 11.  
     [0059] Pharmacoclusters 1 through 8 contain bound conformations of NAD(P)(H) determined from structures deposited in the PDB for NAD(P)(H) bound to oxidoreductase polypeptides. Pharmacoclusters are shown in FIG. 1 and described in further detail in Example I. The pharmacoclusters of FIG. 1 display substantial overlap between bound conformations of NAD(P)(H) within the cluster, as can be identified by visual inspection of the structures. Quantitative comparison of the bound conformations in each pharmacocluster demonstrates that each pharmacocluster displays less than about 1.1 Å difference in RMSD between each conformation of NAD(P)(H) and the average bound conformation for the respective pharmacocluster as described in Example I.  
     [0060] Pharmacoclusters can be used to identify a ligand having specificity for one or more polypeptide pharmacofamilies (see Example V). As described herein, a pharmacophore model or conformer model can be derived from one or more cluster. These models can be used to identify a ligand having specificity for one or more pharmacofamilies of oxidoreductases, for example, by using the model to query a database of molecules for a potential ligand or by using the model to guide in the design of a synthetic ligand. An example of using a pharmacophore of the invention to identify a binding compound is provided in Example VI.  
     [0061] Pharmacoclusters, including, for example, pharmacoclusters 1 through 8 can also be used to identify a new polypeptide member of a polypeptide pharmacofamily. Using the methods described herein, for example, a pharmacocluster can be used to produce a pharmacophore model or conformer model to which a bound conformation of a ligand can be compared. A polypeptide bound to a bound conformation of a ligand that is similar to the model can be classified into an appropriate polypeptide pharmacofamily based on this comparison. By a similar method, a bound conformation of a ligand can be directly compared to a pharmacocluster to classify the polypeptide bound to the conformation of a ligand into an appropriate pharmacofamily.  
     [0062] The methods of the invention can also be used with a portion of a bound conformation of a ligand to identify a pharmacocluster. The method consists of (a) determining a bound conformation of a ligand, or portion thereof, bound to two or more polypeptides, and (b) clustering two or more bound conformations of the ligand, or portion thereof having substantially the same bound conformation, thereby identifying a pharmacocluster.  
     [0063] A bound conformation of a portion of a ligand can include selected atoms and/or bonds of a ligand and can include, for example, a continuous sequence of atoms and/or bonds or a discontinuous sequence of selected atoms and/or bonds that, when described independent of the complete ligand structure, may not appear to be attached to each other. Such a portion can include 2 or more atoms of a bound conformation of a ligand or 3 or more, 4 or more, 5 or more, 6 or more, 7 or more, 8 or more, 9 or more, 10 or more, 15 or more, 20 or more, 25 or more or 50 or more atoms of a bound conformation of a ligand. A bound conformation of a portion of a ligand bound to a polypeptide can be identified according to the same methods described above for identifying a bound conformation of a ligand bound to a polypeptide. Two or more bound conformations of a portion of a ligand can be clustered as described above so long as the bound conformations that are clustered correspond to bound portions of the ligand having the same structural formula. For example, in a case where determination of the complete structure of a ligand has not been achieved, a complete structure of a ligand has not been achieved, a bound conformation of a portion of the ligand corresponding to the structurally determined portion can be used in the methods of the invention.  
     [0064] A pharmacocluster can include portions of bound conformations derived from different ligands so long as the portions have a core bound conformation that is substantially the same. For example, portions having the same structural formula and bond configuration can share a core bound conformation. The bond configuration describes the relative position of atoms attached to a chiral atom of a ligand. Accordingly, R and S sterioisomers of a chiral atom have different bond configurations. Other terms used in the art to designate different bond configurations include, for example, cis and trans configurations of atoms attached to carbons that are double bonded, or Z and E configurations of atoms attached to carbons that are double bonded. An example of portions of ligands having the same structural formula and bond configuration that can share a core bound conformation are the nicotinamide adenine dinucleotide portions of nicotinamide adenine dinucleotide phosphate (NADP) and nicotinamide adenine dinucleotide (NAD). Additionally, portions of ligands having different charge, atom substitution or bond hybridization can share a core bound conformation. An example of portions of ligands having different charge and bond hybridization that can share a core bound conformation are the nicotinamide adenine dinucleotide portions of oxidized nicotinamide adenine dinucleotide (NAD) and reduced nicotinamide adenine dinucleotide (NADH). In cases where the core structures of two ligands bind with substantially the same conformation to polypeptides, the core bound conformations can be clustered according to the methods of the invention (see Example I).  
     [0065] Substantially the same bound conformation of a portion of a bound conformation of a ligand, including non-continuous atoms, can be identified according to the root mean square deviation and compared directly. Conformations of portions having different numbers of atoms can also be compared via root mean square deviation per equivalent atom (RMSD/N, where N is the number of atoms compared). A lower value of RMSD/N indicates increased similarity between the two or more bound ligand conformations that are clustered. One skilled in the art will know that RMSD/N has a compensational origin and consideration of the effect of N is required for comparison of RMSD/N between pharmacoclusters having different values of N. For example, the lower the value of RMSD/N the lower should be the value of N to indicate substantial similarity.  
     [0066] The invention can be used with any ligand for which bound conformations of the ligand bound to different polypeptides can be determined including, for example, chemical or biological molecules such as simple or complex organic molecules, metal-containing compounds, carbohydrates, peptides, peptidomimetics, carbohydrates, lipids, nucleic acids, and the like.  
     [0067] In one embodiment, the compositions and methods of the invention can be used with a ligand that is a nucleotide derivative including, for example, a nicotinamide adenine dinucleotide-related molecule. Nicotinamide adenine dinucleotide-related (NAD-related) molecules that can be used in the methods of the invention can be selected from the group consisting of oxidized nicotinamide adenine dinucleotide (NAD + ), reduced nicotinamide adenine dinucleotide (NADH), oxidized nicotinamide adenine dinucleotide phosphate (NADP + ), and reduced nicotinamide adenine dinucleotide phosphate (NADPH). An NAD-related molecule can also be a mimetic of the above-described molecules. Use of a NAD-related molecule to identify pharmacoclusters is described in Example I.  
     [0068] A mimetic is a molecule that has at least one function that is substantially the same as a function of a second molecule. A mimetic of a ligand can be identified according to its ability to bind to the same sites on a polypeptide as the ligand. For example, a mimetic can be identified by a binding competition assay using a ligand and a mimetic. The structure of a mimetic can be similar or different compared to the structure of the second molecule. The term can encompass molecules having portions similar to corresponding portions of the ligand in terms of structure or function.  
     [0069] Examples of mimetics to the common ligand NADH, for example cibacron blue, are described in  Dye - Ligand Chromatography,  Amicon Corp., Lexington Mass. (1980). Numerous other examples of NADH-mimics, including useful modifications to obtain such mimics, are described in Everse et al. (eds.),  The Pyridine Nucleotide Coenzymes,  Academic Press, New York N.Y. (1982). Particular analogs include nicotinamide 2-aminopurine dinucleotide, nicotinamide 8-azidoadenine dinucleotide, nicotinamide 1-deazapurine dinucleotide, 3-aminopyridine adenine dinucleotide, 3-acetyl pyridine adenine dinucleotide, thiazole amide adenine dinucleotide, 3-diazoacetylpyridine adenine dinucleotide and 5-aminonicotinamide adenine dinucleotide. Particular mimetics can be identified and selected by ligand-displacement assays, for example using competitive binding assays with a known ligand as is well known in the art. Mimetic candidates can also be identified by searching databases of compounds for structural similarity with the common ligand or a mimetic.  
     [0070] In another embodiment, the methods of the invention can be used with a ligand that is an adenosine phosphate-related molecule. Adenosine phosphate-related molecules can be selected from the group consisting of adenosine triphosphate (ATP), adenosine diphosphate (ADP), adenosine monophosphate (AMP), and cyclic adenosine monophosphate (cAMP). An adenosine phophate-related molecule can also be a mimetic of the above-described molecules. A mimetic of an adenosine phosphate-related molecule that can be used in the invention includes, for example, quercetin, adenylylimidodiphosphate (AMP-PNP) or olomoucine.  
     [0071] A ligand useful in the methods of the invention can be a cofactor, coenzyme or vitamin including, for example, NAD, NADP, or ATP as described above. Other examples include thiamine (vitamin B 1 ), riboflavin (vitamin B 2 ), pyridoximine (vitamin B 6 ), cobalamin (vitamin B 12 ), pyrophosphate, flavin adenine dinucleotide (FAD), flavin mononucleotide (FMN), pyridoxal phosphate, coenzyme A, ascorbate (vitamin C), niacin, biotin, heme, porphyrin, folate, tetrahydrofolate, nucleotide such as guanosine triphosphate, cytidine triphosphate, thymidine triphosphate, uridine triphosphate, retinol (vitamin A), calciferol (vitamin D 2 ), ubiquinone, ubiquitin, α-tocopherol (vitamin E), farnesyl, geranylgeranyl, pterin, pteridine or S-adenosyl methionine (SAM).  
     [0072] A polypeptide can be used as a ligand in the invention. For example, a ligand can be a naturally occurring polypeptide ligand such as a ubiquitin or polypeptide hormone including, for example, insulin, human growth hormone, thyrotropin releasing hormone, adrenocorticotropic hormone, parathyroid hormone, follicle stimulating hormone, thyroid stimulating hormone, luteinizing hormone, human chorionic gonadotropin, epidermal growth factor, nerve growth factor and the like. In addition a polypeptide ligand can be a non-naturally occurring polypeptide that has binding activity. Such polypeptide ligands can be identified, for example, by screening a synthetic polypeptide library such as a phage display library or combinatorial polypeptide library as described below. A polypeptide ligand can also contain amino acid analogs or derivatives such as those described below. Methods of isolation of a polypeptide ligand are well known in the art and are described, for example, in Scopes,  Protein Purification: Principles and Practice,  3 rd  Ed., Springer-Verlag, New York (1994); Duetscher,  Methods in Enzymology,  Vol 182, Academic Press, San Diego (1990); and Coligan et al.,  Current protocols in Protein Science,  John Wiley and Sons, Baltimore, Md. (2000).  
     [0073] A nucleic acid can also be used as a ligand in the invention. Examples of nucleic acid ligands useful in the invention include DNA, such as genomic DNA or cDNA or RNA such as mRNA, ribosomal RNA or tRNA. A nucleic acid ligand can also be a synthetic oligonucleotide. Such ligands can be identified by screening a random oligonucleotide library for ligand binding activity, for example, as described below. Nucleic acid ligands can also be isolated from a natural source or produced in a recombinant system using well known methods in the art including, for example, those described in Sambrook et al.,  Molecular Cloning: A Laboratory Manual,  2nd ed., Cold Spring Harbor Press, Plainview, N.Y. (1989); Ausubel et al.,  Current Protocols in Molecular Biology  (Supplement 47), John Wiley &amp; Sons, New York (1999).  
     [0074] A ligand used in the invention can be an amino acid, amino acid analog or derivatized amino acid. An amino acid ligand can be one of the 20 essential amino acids or any other amino acid isolated from a natural source. Amino acid analogs useful in the invention include, for example, neurotransmitters such as gamma amino butyric acid, serotonin, dopamine, or norepenephrine or hormones such as thyroxine, epinephrine or melatonin. A synthetic amino acid, or analog thereof, can also be used in the invention. A synthetic amino acid can include chemical modifications of an amino acid such as alkylation, acylation, carbamylation, iodination, or any modification that derivatizes the amino acid. Such derivatized molecules include, for example, those molecules in which free amino groups have been derivatized to form amine hydrochlorides, p-toluene sulfonyl groups, carbobenzoxy groups, t-butyloxycarbonyl groups, chloroacetyl groups or formyl groups. Free carboxyl groups can be derivatized to form salts, methyl and ethyl esters or other types of esters or hydrazides. Free hydroxyl groups can be derivatized to form O-acyl or O-alkyl derivatives. The imidazole nitrogen of histidine can be derivatized to form N-im-benzylhistidine. Naturally occurring amino acid derivatives of the twenty standard amino acids can also be included in a cluster of bound conformations including, for example, 4-hydroxyproline, 5-hydroxylysine, 3-methylhistidine, homoserine, ornithine or carboxyglutamate.  
     [0075] A lipid ligand can also be used in the invention. Examples of lipid ligands include triglycerides, phospholipids, glycolipids or steroids. Steroids useful in the invention include, for example, glucocorticoids, mineralocorticoids, androgens, estrogens or progestins.  
     [0076] Another type of ligand that can be used in the invention is a carbohydrate. A carbohydrate ligand can be a monosaccharide such as glucose, fructose, ribose, glyceraldehyde, or erythrose; a disaccharide such as lactose, sucrose, or maltose; oligosaccharide such as those recognized by lectins such as agglutinin, peanut lectin or phytohemagglutinin, or a polysaccharide such as cellulose, chitin, or glycogen.  
     [0077] Methods for producing pluralities of compounds to use as ligands, including chemical or biological molecules such as simple or complex organic molecules, metal-containing compounds, carbohydrates, peptides, peptidomimetics, carbohydrates, lipids, nucleic acids, and the like, are well known in the art (see, for example, in Huse, U.S. Pat. No. 5,264,563; Francis et al.,  Curr. Opin. Chem. Biol.  2:422-428 (1998); Tietze et al.,  Curr. Biol.,  2:363-371 (1998); Sofia,  Mol. Divers.  3:75-94 (1998); Eichler et al.,  Med. Res. Rev.  15:481-496 (1995); Gordon et al.,  J. Med. Chem.  37: 1233-1251 (1994); Gordon et al.,  J. Med. Chem.  37: 1385-1401 (1994); Gordon et al.,  Acc. Chem. Res.  29:144-154 (1996); Wilson and Czarnik, eds.,  Combinatorial Chemistry: Synthesis and Application,  John Wiley &amp; Sons, New York (1997), Gold et al., U.S. Pat. Nos. 5,475,096 (1995), 5,789,157 (1998), and 5,270,163 (1993)). The advantage of using such a combinatorial library is that molecules do not have to be individually generated to identify a ligand that binds a polypeptide. Also, no prior knowledge of the exact characteristics of a binding polypeptide is required when using a combinatorial library. Libraries containing large numbers of natural and synthetic compounds also can be individually synthesized or obtained from commercial sources.  
     [0078] In addition, the invention provides a method for identifying a conformation-dependent property of a ligand. The method includes the steps of (a) determining bound conformations of a ligand bound to different polypeptides; (b) identifying two or more bound conformations of the ligand having substantially the same bound conformation, and (c) identifying a conformation-dependent property of the bound conformations of the ligand having substantially the same bound conformation, the conformation-dependent property being correlated with the bound conformation of the ligand.  
     [0079] A conformation-dependent property can be identified as any property that correlates with a bound conformation of a ligand such that a change in the bound conformation results in a change in the conformation-dependent property. Accordingly, a bound conformation of a ligand, or a portion thereof, can be a conformation-dependent property. A portion of a bound conformation of a ligand can be a contiguous fragment or a non-contiguous set of atoms or bonds. A bound conformation of a ligand, or portion thereof, can be identified by any method for determining the three dimensional structure of a ligand including as disclosed herein.  
     [0080] Other conformation-dependent properties include, for example, absorption and emission of heat, absorption and emission of electromagnetic radiation, rotation of polarized light, magnetic moment, spin state of electrons, or polarity, as disclosed herein, or other properties that can be identified as a spectroscopic signal. Methods known in the art for measuring changes in absorption and emission of heat that correlate with changes in bound conformation of a ligand include, for example, calorimetry. Methods known in the art for measuring changes in absorption and emission of electromagnetic radiation as they correlate with changes in bound conformation of a ligand include, for example, UV/VIS spectroscopy, fluorimetry, luminometry, infrared spectroscopy, Raman spectroscopy, resonance Raman spectroscopy, X-ray absorption fine structure spectroscopy (XAFS) and the like. A change in a bound conformation of a ligand that is correlated with a change in rotation of polarized light can be measured with circular dichroism spectroscopy or optical rotation spectroscopy. A change in magnetic moment or spin state of an electron that correlates with a change in a bound conformation can be measured, for example, with Electron paramagnetic resonance spectroscopy (EPR) or nuclear magnetic resonance spectroscopy (NMR).  
     [0081] When based on NMR data, a conformation-dependent property can be identified as an NMR signal including, for example, chemical shift, J coupling, dipolar coupling, cross-correlation, nuclear spin relaxation, transferred nuclear Overhauser effect, and any combination thereof. A conformation-dependent property can be identified by NMR methods in both fast and slow exchange regimes. For example, in many cases, the exchange rate of a complex between ligand and polypeptide is faster than the ligand spin relaxation rate (1/T 1H ). In this situation, referred to as the “fast exchange regime,” transferred nuclear Overhauser effect (NOE) experiments can be performed to measure an intra-ligand proton-proton distance (Wuthrich,  NMR of proteins and Nucleic Acids,  Wiley, New York (1986) and Gronenborn,  J. Magn. Res.  53:423-442 (1983)). Labeling of polypeptides is not required, and the ligand polypeptide concentration ratio can be adjusted to minimize line broadening of the ligand resonances while retaining strong NOE contribution from the bound form.  
     [0082] In a fast exchange regime, cross-correlated relaxation measurements can also provide structural information on ligand torsion angles (Carlomagno et al.,  J. Am. Chem Soc.  121:1945-1948 (1999)). These measurements include the  1 H- 1 H dipole-dipole cross-correlation but can be extended to other cross-correlated relaxation mechanisms involving also homo- and heteronuclear chemical shielding anisotropy relaxation, as well as quadrupolar relaxation. For most of these heteronuclear experiments, the natural abundance of the isotope can be exploited. In cases where natural abundance of the isotope measured is not sufficient, isotope enriched ligands can be obtained from commercial sources such as Isotek (Miamisburg, Ohio) or Cambridge Isotope Laboratories (Andover, Mass.) or prepared by methods known in the art. Another method to determine a conformation-dependent property of a ligand in a fast exchange regime is use of residual homo- and heteronuclear dipolar couplings in partially aligned samples (Tolman et al.  Proc. Natl. Acad. Sci. USA  92:9279-9283 (1995)).  
     [0083] In the slow exchange regime, the NMR signals arising from the bound conformation of the ligand are distinguished from those of the polypeptide to reduce resonance overlap. This can be achieved with different isotope labeling schemes of polypeptide, ligand or both. For large systems, perdeuteration of macromolecules and TROSY-type experiments (Pervushkin,  Proc. Natl. Acad. Sci. USA  94:12366-12371 (1997)) can be used to minimize signal losses due to fast transverse relaxation of the resonances of the complex. With the appropriate sample requirements and isotope filtered experiments, cross-correlations, cross-relaxations and residual dipolar couplings can be measured and provide necessary structural information.  
     [0084] In addition, homo- and heteronuclear two and three bond J couplings can be obtained to provide information on torsion angles (Wuthrich, supra). For example, as shown in Table 1 the bound conformations of NADP in pharmacocluster 4 and pharmacocluster 5 differ by a torsion angle defined by the atoms PN-O5′N-C5′N-C4′N (See FIG. 2 for atom labeling and bond location). Specifically, pharmacocluster 4 has a PN-O5′N-C5′N-C4′N torsion angle of 145 degrees and pharmacocluster 5 has a PN-O5′N-C5′N-C4′N angle of −112 degrees. These torsion angles can be measured and distinguished by measuring the three bond  31 P- 13 C4′ J coupling constants that correspond to this torsion angle (Marino,  Acc. Chem. Res.  32:614-623 (1999)). Basically, two 1H- 13 C correlation experiments can be performed with and without 31P decoupling during  13 C evolution. The intensity ratio of the  1 H 4′/ 13 C4′ cross peak from each experiment is proportional to the  31 P- 13 C4′ J coupling constant.  
     [0085] Correlation of a conformation-dependent property with a bound conformation of a ligand can be achieved by any method that has sufficient sensitivity to detect changes that correlate with changes in bound conformation of a ligand. Such a correlation can be determined by measuring a conformation-dependent property for various conformations of a ligand and determining the extent of change in the signal with change in the conformation. Signal changes that correlate with changes in conformation and that are detectable with a signal to noise ratio accepted in the art as significant can be used in the invention.  
     [0086] Correlation between a conformation-dependent property and a conformation can be determined for a ligand bound to any partner so long as binding is specific and stable. For example, for purposes of establishing a correlation, changes in a conformation dependent property that correlate with changes in bound conformation of a ligand can be determined for a ligand bound to polypeptides from different polypeptide pharmacofamilies. A bound conformation of the ligand in each complex can be determined and a conformation-dependent property can be measured for each complex. Comparison of bound conformations of the ligand in each complex with a measured conformation-dependent property can be used to establish a correlation. Demonstration of a method for establishing a correlation between an NMR signal and bound conformations of a ligand is described herein (see Example IV). Other methods for correlating spectroscopic signals with bound conformations of a ligand are known in the art including, for example, correlation of transferred NOE signals with anti and syn conformations of the nicotinamide ring in NADPH as described in Sem and Kasper  Biochemistry  31:3391-3398 (1992). Correlation of transferred NOE signals with conformation is also described in Clore and Gronenborn,  J. Magn. Reson.  48:402-417 (1982).  
     [0087] A correlation between a bound conformation and a conformation-dependent property can also be established for a ligand bound to a non-polypeptide binding partner because a conformation-dependent property of a ligand can be independent of interactions that differ between binding partners so long as the ligand is in the same bound conformation when bound to the binding partners. Other binding partners include, for example, nucleic acids, carbohydrates, and synthetic organometallic complexes.  
     [0088] A method of the invention for identifying a conformation-dependent property of a ligand can also include the steps of (a) determining a bound conformation of a ligand, or portion thereof, bound to two or more polypeptides; (b) identifying two or more bound conformations of the ligand, or portion thereof, having substantially the same bound conformation, and (c) identifying a conformation-dependent property of the bound conformations of the ligand, or portion thereof, having substantially the same bound conformation, the conformation-dependent property being correlated with the bound conformation of the ligand, or portion thereof. A conformation-dependent property of a portion of a ligand can be identified, for example, by using the methods described above for identifying a conformation-dependent property of a ligand.  
     [0089] The invention also provides a method for identifying a polypeptide pharmacofamily. The method includes the steps of (a) determining bound conformations of a ligand bound to different polypeptides of a polypeptide family, and (b) identifying two or more bound conformations of the ligand having substantially different bound conformations, thereby identifying at least two polypeptide pharmacofamilies exhibiting binding specificity for the two or more substantially different bound conformations of the ligand.  
     [0090] A method for identifying a polypeptide pharmacofamily can include the steps of (a) determining bound conformations of a ligand bound to different polypeptides of a polypeptide family; (b) clustering bound conformations of a ligand having substantially the same conformations into pharmacoclusters; and (c) identifying a first polypeptide that binds a bound conformation of a ligand in one pharmacocluster and a second polypeptide that binds a bound conformation of a ligand in a second pharmacocluster as belonging to separate polypeptide pharmacofamilies.  
     [0091] Polypeptides of a polypeptide family can be identified by their ability to specifically bind to the same ligand, or portion thereof. Specific binding between a polypeptide and a ligand can be identified by methods known in the art. Methods of determining specific binding include, for example, equilibrium binding analysis, competition assays, and kinetic assays as described in Segel,  Enzyme Kinetics  John Wiley and Sons, New York (1975), and Kyte,  Mechanism in Protein Chemistry  Garland Pub. (1995). Thermodynamic and kinetic constants can be used to identify and compare polypeptides and ligands that specifically bind each other and include, for example, dissociation constant (K d ), association constant (K a ) Michaelis constant (K m ), inhibitor dissociation constant (K is ) association rate constant (k on ) or dissociation rate constant (k off ). For example, a family can be identified as having members that can specifically bind a ligand with a K d  of at most 10 −3  M, 10 −4  M, 10 −5  M, 10 −6  M, 10 −7  M, 10 −8  M, 10 −9  M, 10 −10  M, 10 −11  M, or 10 −12  M or lower.  
     [0092] A family of polypeptides that bind a ligand can contain a pharmacofamily that binds substantially the same conformation of the ligand, or portion thereof. The methods can be used to identify any number of pharmacofamilies in a family according to the number of different bound conformations of a ligand identified. In cases where two or more polypeptide pharmacofamilies reside in a polypeptide family, the pharmacofamilies can be distinguished according to differences in bound conformations of a ligand bound to the polypeptides. In this case, a bound conformation of a ligand can be determined and compared according to the methods described herein. Polypeptides bound to different bound conformations of a ligand can be identified as those that do not show substantial overlap of all corresponding atoms when bound conformations are overlaid. Thus, polypeptides that bind different bound conformations of a ligand can be separated into different pharmacofamilies. Pharmacofamilies in turn can be identified as containing polypeptides that bind substantially the same bound conformation of a ligand (see Examples II and III).  
     [0093] A pharmacofamily of polypeptides identified by the methods of the invention can have additional similarities that correlate with similarities in bound conformation of a ligand. For example, a polypeptide pharmacofamily identified by the methods of the invention can consist of polypeptide members that share characteristics that are unique to the pharmacofamily when compared to one or more other polypeptides in a different pharmacofamily of the same family. Such characteristics can include, for example, protein fold, evolutionary relatedness, enzymatic activity, domain structure, subcellular localization, interaction partners, or participation in a similar metabolic or signal transduction pathway. A demonstration of a correlation between ligand bound conformation and another characteristic of polypeptides in a pharmacofamily is provided in Example II, which describes correlation of bound conformation of a ligand with polypeptide structure.  
     [0094] An example of a polypeptide family having multiple pharmacofamilies that can be identified by the methods of the invention includes NAD(P)(H) binding polypeptides. Polypeptide pharmacofamilies identified according to differences in bound conformations of NAD(P)(H) are described in Example II and Table 11. Thus, the methods can be used to identify a polypeptide pharmacofamily selected from the group consisting of pharmacofamily 1, pharmacofamily 2, pharmacofamily 3, pharmacofamily 4, pharmacofamily 5, pharmacofamily 6, pharmacofamily 7, and pharmacofamily 8.  
     [0095] The invention provides a polypeptide pharmacofamily, comprising polypeptides that bind to substantially the same bound conformation of a nicotinamide adenine dinucleotide-related molecule selected from pharmacofamily 1, pharmacofamily 2, pharmacofamily 3, pharmacofamily 4, pharmacofamily 5, pharmacofamily 6, pharmacofamily 7, and pharmacofamily 8 as listed in Table 11.  
     [0096] Pharmacofamilies 1 through 8 consist of the polypeptide members provided in Table 11 (see Example II). The polypeptides in pharmacofamily 1 have the NAD(P)(H) binding Rossman fold in common, are all in the NAD(P)(H) binding Rossman SCOP Superfamily, and fall into the SCOP families of the amino-terminal domain of glyceraldehyde-3-phosphate dehydrogenase, the carboxy-terminal domain of alcohol/glucose dehydrogenase, the NAD binding domain of formate/glycerate dehydrogenase, the carboxy-terminal domain of amino acid dehydrogenase, or the amino-terminal domain of lactate &amp; malate dehydrogenase.  
     [0097] The polypeptides in pharmacofamily 2 have the NAD(P)(H) binding Rossman fold in common, are all in the NAD(P)(H) binding Rossman SCOP Superfamily, and fall into the SCOP families of the carboxy-terminal domain of amino acid dehydrogenase, glyceraldehyde 3-phosphate dehydrogenase, and 6-phosphogluconate dehydrogenase.  
     [0098] The polypeptides in pharmacofamily 3 have the NAD(P)(H) binding Rossman fold in common, are all in the NAD(P)(H) binding Rossman SCOP Superfamily, and fall into the tyrosine-dependent oxidoreductase SCOP family.  
     [0099] The polypeptides in pharmacofamily 4 have the heme-linked catalase fold and are in the heme-linked catalase SCOP superfamily and heme-linked catalase SCOP family.  
     [0100] The polypeptides in pharmacofamily 5 have the β-α TIM barrel fold in common, are all in the NAD(P)(H) linked oxidoreductase SCOP Superfamily, and fall into the aldo-keto reductase SCOP family.  
     [0101] The polypeptides in pharmacofamily 6 are dihydrofolate reductases that all show the dihydrofolate reductase fold and fall into the dihydrofolate reductase SCOP superfamily and family.  
     [0102] The polypeptides in pharmacofamily 7 have the FAD/NAD(P)(H) binding domain fold in common, are all in the FAD/NAD(P)(H) binding domain SCOP Superfamily, and fall into the the amino-terminal and central domains of FAD/NAD linked reductase SCOP family.  
     [0103] The polypeptides in pharmacofamily 8 have the ferrodoxin like fold in common, are all in the ferrodoxin like SCOP Superfamily, and fall into the NADPH-cytochrome P450 reductase or reductase SCOP families.  
     [0104] Polypeptide pharmacofamilies 1 through 8 were identified according to binding interactions with bound conformations of NAD(P)(H) in pharmacoclusters 1 through 8, as described in Example II. Accordingly, the invention provides a polypeptide pharmacofamily, comprising polypeptides that bind to a nicotinamide adenine dinucleotide-related molecule having a bound conformation selected from pharmacocluster 1, pharmacocluster 2, pharmacocluster 3, pharmacocluster 4, pharmacocluster 5, pharmacocluster 6, pharmacocluster 7, and pharmacocluster 8.  
     [0105] The invention additionally provides a method for identifying a member of a polypeptide pharmacofamily. The method consists of (a) determining a conformation-dependent property of a ligand bound to a polypeptide, and (b) determining a pharmacocluster having substantially the same conformation-dependent property as the conformation-dependent property determined for the bound ligand, wherein a polypeptide pharmacofamily binds the ligand in a conformation of the pharmacocluster, thereby identifying the polypeptide as a member of the polypeptide pharmacofamily. For example, the method can be used with a ligand such as a nicotinamide adenine dinucleotide-related molecule or adenosine phosphate-related molecule (see Examples II and III).  
     [0106] The methods of the invention allow a new member of a polypeptide pharmacofamily to be identified based on correlation of a conformation-dependent property of a bound conformation of a ligand bound to a polypeptide with a conformation-dependent property established for a bound conformation of the ligand bound to another polypeptide in the same pharmacofamily. Thus, a classification can be made based on ligand structure without requiring determination of the bound conformation of the ligand. In one embodiment, the conformation-dependent property can be a model of a bound conformation. A bound conformation of a ligand bound to a test polypeptide can be determined, and the bound conformation can be compared to a pharmacocluster according to the methods described herein. Substantial overlap between the bound conformation of the ligand bound to the test polypeptide and another bound conformation of the ligand bound to a polypeptide in a pharmacofamily can be used to identify the test polypeptide as a member of that polypeptide pharmacofamily.  
     [0107] In another embodiment, the conformation-dependent property can be a spectroscopic signal that is correlated with the conformation of a ligand. A spectroscopic signal can be measured for the ligand bound to a test polypeptide. The signal can be compared to a signal correlated with a bound conformation of a ligand bound to a polypeptide in a polypeptide pharmacofamily. Substantial similarity between the two signals indicates that the bound conformation of the ligand bound to the test polypeptide is substantially similar to the bound conformation of the ligand bound to the polypeptides of the pharmacofamily. Thus, the test polypeptide can be identified as a member of the polypeptide pharmacofamily.  
     [0108] The invention provides rapid and efficient methods that can be used in a high-throughput screening format. High-throughput methods can be useful for identifying a member of a polypeptide pharmacofamily. In a case where a conformation-dependent property can be rapidly detected and processed, automated methods can be created for measuring samples in rapid succession or measuring multiple samples in parallel. Automated methods can be used for rapidly handling samples including, for example, robotic instruments. A combination of automated sample handling methods with detection of a conformation-dependent property can, therefore, be useful in a high-throughput screening method.  
     [0109] According to the methods of the invention a compound can be identified that has greater specificity for the polypeptides of one pharmacofamily than for other polypeptides in the same family. Such a compound can be used to identify new members of a pharmacophore family using a binding assay. For example, a mimetic or analog of a ligand can be identified that preferentially adopts a conformation more similar to conformations in a particular pharmacocluster than those in other pharmacoclusters. Such a mimetic or analog can be used in a any binding assay capable of detecting interactions with a polypeptide, including, for example, high-throughput methods.  
     [0110] A member of a polypeptide pharmacofamily can also be identified by searching a database of bound conformations of a ligand. For example, a bound conformation of a ligand that binds to a polypeptide of an identified pharmacofamily can be used as a query in a 3 dimensional search of a database containing bound conformations of a ligand. Overlap between the query conformation and a retrieved bound conformation of the ligand can be used to identify a polypeptide bound to the retrieved bound conformation of the ligand as a member of the same polypeptide pharmacofamily as a polypeptide that binds the query bound conformation (see Example I).  
     [0111] The invention also provides a method of modeling the three dimensional structure of a polypeptide. The method consists of (a) determining a conformation-dependent property of a ligand bound to a polypeptide; (b) determining a pharmacocluster having substantially the same conformation-dependent property as the conformation-dependent property determined for the bound ligand, wherein a polypeptide pharmacofamily binds the ligand in a conformation of the pharmacocluster, thereby identifying the polypeptide as a member of the polypeptide pharmacofamily, and (c) modeling the three dimensional structure of the polypeptide according to a structural model of the second member of the polypeptide pharmacofamily.  
     [0112] As disclosed herein, polypeptides in a pharmacofamily can have similar characteristics including, for example, similar 3 dimensional structure. Therefore, the 3 dimensional structure of a polypeptide identified by the invention as a member of a pharmacofamily can be modeled using a polypeptide that is in the same pharmacofamily and for which the structure is known. A variety of methods are known in the art for modeling the three dimensional structure of a polypeptide according to the amino acid sequence of the polypeptide and a structure of a second polypeptide used as a template. Available algorithms include, for example, GRASP (Nicholls, A., supra), ALADDIN (Van Drie et al. supra), INSIGHT98 (Molecular Simulations Inc., San Diego Calif.), RASMOL (Sayle et al.,  Trends Biochem Sci.  20:374-376 (1995)) and MOLMOL (Koradi et al.,  J. Mol. Graphics  14:51-55 (1996)).  
     [0113] A model of a polypeptide determined by the methods of the invention can be useful for identifying a function of the polypeptide. For example, residues of a polypeptide that are involved in binding can be identified using a model of the invention. Residues identified as participating in binding can be modified, for example, to engineer new functions into a polypeptide, to reduce an intrinsic activity of a polypeptide, or to enhance an intrinsic activity of a polypeptide. In another example, a model of a polypeptide can be compared to other polypeptide structures to identify similar functions. Exemplary functions that can be identified from a polypeptide structure include binding interactions with other polypeptides and catalytic activities.  
     [0114] The invention also provides a method for constructing a ligand conformer model by determining an average structure of the bound conformations of a ligand in a pharmacocluster. A method for constructing a ligand conformer model can include the steps of (a) determining bound conformations of a ligand bound to different polypeptides; (b) clustering two or more bound conformations of the ligand having substantially the same bound conformation, thereby identifying a pharmacocluster, and (c) determining an average structure of the bound conformations of the ligand in the pharmacocluster. Additionally, a method for constructing a ligand conformer model can include the steps of (a) determining a bound conformation of a ligand bound to a polypeptide; (b) determining a pharmacocluster having substantially the same bound conformation as the bound conformation, thereby identifying the bound conformation of the ligand as a member of the pharmacocluster, and (c) determining an average structure of the bound conformations of the ligand in the pharmacocluster.  
     [0115] An average structure of the bound conformations of a ligand in a pharmacocluster can be determined by a variety of methods known in the art. For example, an average structure can be determined by overlaying bound conformations, or portions thereof, and identifying an average location for each atom. Bound conformations in a group to be averaged can be overlayed relative to a single member or relative to a centroid position for each atom. Algorithms for determining an average structure are known in the art and include for example the OVERLAY routine in INSIGHT98 (Molecular Simulations Inc., San Diego Calif.).  
     [0116] The format of a ligand conformer model can be chosen based on the method used to generate the model and the desired use of the model. In this regard, a conformer model can be represented as a single structure. The resulting structure can be a unique structure compared to the conformations in the pharmacocluster from which it was derived. Thus, the conformer model can be a new structure never before observed in nature. A model represented by a single structure can be useful for making visual comparisons by overlaying other structures with the model. A conformer model can also be represented as a plurality of structures incorporating all or a subset of the bound conformations in the pharmacocluster. A model represented by multiple structures can be useful for identifying a range of minor deviations in the model.  
     [0117] In yet another representation, the conformer model can be a volume surrounding all or a subset of the bound conformations in the pharmacocluster. A model showing volume can be useful for comparing other structures in a fitting format such that a structure which fits within the volume of the model can be identified as substantially similar to the model. One approach that can be used to fit a structure to a volume is comparison of equivalent surface patches using gnomonic projection as described for example in Chau and Dean,  J. Mol. Graphics  7:130 (1989). Use of a gnomonic projection to compare structures is also described in Doucet and Weber,  Computer - Aided Molecular Design: Theory and Applications,  Academic Press, San Diego Calif. (1996). Algorithms which can be used to fit a structure to a volume are known in the art and include, for example, CATALYST (Molecular Simulations Inc., San Diego, Calif.) and THREEDOM which is a part of the INTERCHEM package which makes use of an Icosahedral Matching Algorithm (Bladon,  J. Mol. Graphics  7:130 (1989) for the comparison and alignment of structures. An exemplary method of identifying a binding compound by searching a database of structures using a gnomonic projection is provided in Example V.  
     [0118] A conformer model can be useful in querying a database of polypeptide structures to find other members of a polypeptide pharmacofamily. For example, a member of a polypeptide pharmacofamily can be identified by querying a database of bound conformations of a ligand to identify a retrieved bound conformation of a ligand that is substantially similar to the query structure, thereby identifying a polypeptide bound to the retrieved bound conformation as a member of the same pharmacofamily as a polypeptide bound to the query bound conformation. A conformer model can also be used to identify a new member of a polypeptide pharmacofamily by querying a database of one or more polypeptide structures using an algorithm that docks the conformer model, wherein a favorable docking result with a retrieved polypeptide indicates that the retrieved polypeptide is a member of the same polypeptide pharmacofamily as a polypeptide bound to the bound conformation used as a query. In the latter mode, a potential new member of a pharmacofamily from which the conformer model was derived can be identified. The database queries described above can be performed with algorithms available in the art including, for example, THREEDOM and CATALYST.  
     [0119] An advantage of the invention is that a conformer model can be used to identify a binding compound that is specific for polypeptides of a pharmacofamily. For example, the conformer model can be compared to a structure of a compound or to a bound conformation of a ligand to identify those having similar conformation. A conformer model can be further used to query a database of compounds to identify individual compounds having similar conformations.  
     [0120] A conformer model of the invention can also be used to design a binding compound that is specific for polypeptides of one or more pharmacofamilies. The methods of the invention provide a conformer model that can be produced according to a cluster of bound conformations of a ligand that are specific for polypeptides of a pharmacofamily. A conformer model identified by these criteria can be used as a scaffold structure for developing a compound having enhanced binding affinity or specificity for polypeptides of a pharmacofamily. Such a scaffold can also be used to design a combinatorial synthesis producing a library of compounds which can be screened for enhanced binding affinity for polypeptide members of a pharmacofamily or specificity for polypeptide members of one pharmacofamily compared to polypeptide members of another pharmacofamily. An algorithm can be used to design a binding compound based on a conformer model including, for example, LUDI as described by Bohm,  J. Comput. Aided Mol. Des.  6:61-78 (1992).  
     [0121] A conformer model need not include all atoms of a pharmacocluster. Thus, a conformer model can include a portion of atoms in a pharmacocluster so long as the portion consists of contiguous atoms of a bound conformation of a ligand and provides sufficient information to distinguish one pharmacocluster from another. Thus, a conformer model can be constructed by overlaying corresponding fragments of bound conformations of a ligand and obtaining an average structure according to the methods described above. A conformer model made from a portion of a ligand can be advantageous due to its small size compared to a complete structure of the ligand from which it was derived. A conformer model based on a portion of a bound conformation of a ligand can also be used to more efficiently and rapidly query a database due to a reduced use of computer memory compared to the memory required to manipulate and store a structure containing all atoms of the ligand.  
     [0122] The invention provides a ligand conformer model, selected from the group consisting of conformer model 1 having coordinates listed in Table 3C, conformer model 2 having coordinates listed in Table 4C, conformer model 3 having coordinates listed in Table 5C, conformer model 4 having coordinates listed in Table 6C, conformer model 5 having coordinates listed in Table 7C, conformer model 6 having coordinates listed in Table 8C, conformer model 7 having coordinates listed in Table 9C, and conformer model 8 having coordinates listed in Table 1° C. Conformer models 1-8 are average structures calculated from pharmacoclusters 1-8 respectively. The conformer models were determined as described in Example III and are shown in FIG. 4.  
     [0123] The invention also provides moiety, having coordinates listed in Table 3C, coordinates listed in Table 4C, coordinates listed in Table 5C, coordinates listed in Table 6C, coordinates listed in Table 7C, coordinates listed in Table 8C, coordinates listed in Table 9C, or coordinates listed in Table 10C or subsets of the respective coordinate sets thereof. In one embodiment the moiety is not nicotinamide adenine dinucleotide or nicotinamide adenine dinucleotide phosphate.  
     [0124] Additionally, the invention provides a method for constructing a pharmacophore model by constructing a model that contains one or more selected conformation-dependent properties of one or more pharmacoclusters. A method for constructing a pharmacophore model can include the steps of (a) determining bound conformations of a ligand bound to different polypeptides; (b) identifying two or more bound conformations of the ligand having substantially the same bound conformation; (c) identifying a conformation-dependent property of the bound conformations of the ligand having substantially the same bound conformation, the conformation-dependent property being correlated with the bound conformation of the ligand, and (d) constructing a model that contains one or more selected conformation-dependent properties of one or more pharmacoclusters.  
     [0125] Additionally, a method for constructing a pharmacophore model can include the steps of (a) determining bound conformations of a ligand, or portion thereof, bound to different polypeptides; (b) clustering two or more bound conformations of the ligand, or portion thereof, having substantially the same bound conformation, thereby identifying a pharmacocluster, and (c) determining an average structure of the bound conformations of the ligand, or portion thereof, in the pharmacocluster, wherein the average structure is a pharmacophore model. A method for constructing a ligand conformer model can also include the steps of (a) determining a bound conformation of a ligand, or portion thereof, bound to a polypeptide; (b) determining a pharmacocluster having substantially the same bound conformation as the bound conformation, thereby identifying the bound conformation of the ligand as a member of the pharmacocluster, and (c) determining an average structure of the bound conformations of the ligand in the pharmacocluster, wherein the average structure is a pharmacophore model.  
     [0126] A pharmacophore model constructed by the methods of the invention can be derived from any conformation-dependent property that is correlated with a pharmacocluster. An example of a pharmacophore model useful in the methods of the invention is a conformer model. Additionally, a pharmacophore model can include a portion of a bound conformation, wherein the portion need not contain contiguous atoms of a bound conformation of a ligand so long as the pharmacophore model provides sufficient information to distinguish one pharmacocluster from another. Thus, a pharmacophore model can appear as points in space unconnected by any semblance of a covalent bond due to absence of intervening atoms. For example, a pharmacophore model constructed from a pharmacocluster of nicotinamide adenine dinucleotide bound conformations can contain a phosphate moiety and nicotinamide ring moiety absent the ribose moiety which intervenes in a complete model of the structure.  
     [0127] A pharmacophore model can be any representation of points in a defined coordinate system that correspond to positions of atoms in a bound conformation of a ligand. For example, a point in a pharmacophore model can correlate with the center of an atom in a conformer model. An atom of a conformer model can also be represented by a series of points forming a line, plane or sphere. A line, plane or sphere can form a geometric representation designating, for example, shape of one or more atoms or volume occupied by one or more atoms.  
     [0128] A pharmacophore model can be represented in any coordinate system including, for example, a 2 dimensional Cartesian coordinate system or 3 dimensional Cartesian coordinate system. Other coordinate systems that can be used include a fractional coordinate system or reciprocal space such as those used in crystallographic calculations which are described in Stout and Jensen, supra.  
     [0129] In addition to a geometric description of a bound conformation of a ligand, a pharmacophore model can include other characteristics of atoms or moieties of the ligand including, for example, charge or hydrophobicity. Thus, a pharmacophore model can be a generalized structure, which includes but does not unambiguously describe the bound conformations of the ligand bound to the polypeptides in the pharmacofamily from which it was derived. For example, atoms can be represented as units of charge such that an oxygen in a bound conformation of a ligand can be represented by an electronegative point in the pharmacophore model. In this example, the electronegative point in the pharmacophore model includes any electronegative atom at that particular location including, for example, an oxygen or sulfur.  
     [0130] A pharmacophore model can be constructed to include, in addition to characteristics of the ligand itself, characteristics of an atom or moiety that interacts with the ligand and from a bound polypeptide. Characteristics of an interacting polypeptide atom or moiety that can be included in a pharmacophore model include, for example, atomic number, volume occupied, distance from an atom of the ligand, charge, hydrophobicity, polarity, or location relative to the ligand. Methods for constructing a pharmacophore model to include interacting atoms from a polypeptide are provided in Example III.  
     [0131] A characteristic included in a pharmacophore model can be incorporated into a geometric representation using any additional representation that can be correlated with the characteristic. For example, use of color or shading can be used to identify regions having characteristics such as charge, polarity, or hydrophobicity. As such, the depth of shading or color or the hue of color can be used to determine the degree of a characteristic. By way of example, a common convention used in the art is to identify regions of increased positive charge with deeper shades of blue, areas of increased negative charge with deeper shades of red and neutral regions with white. Numeric representations can also be used in a pharmacophore model including, for example, values corresponding to potential energy for an interaction, or degree of polarity.  
     [0132] In addition, a pharmacophore model can incorporate constraints of a physical or chemical property of the bound conformations of a ligand in a pharmacocluster. A constraint of a physical property can be, for example, a distance between two atoms, allowed torsion angle of a bond, or volume of space occupied by an atom or moiety. A constraint of a chemical property can be, for example, polarity, van der Waals interaction, hydrogen bond, ionic bond, or hydrophobic interaction. Such constraints can be included in a pharmacophore model using the representations described above.  
     [0133] A pharmacophore model can include two or more pharmacoclusters. In order to identify a ligand having broad specificity for two or more polypeptide pharmacofamilies, a pharmacophore model can be derived from the two or more corresponding pharmacoclusters. Additionally, in order to identify a ligand that can preferentially bind a first polypeptide which belongs to a first polypeptide pharmacofamily compared to a second polypeptide of a second polypeptide pharmacofamily, a pharmacophore model can incorporate constraints on geometry or any other characteristic so as to exclude a characteristic of the bound conformation of the ligand bound to the second polypeptide. For example, a geometric constraint can be a forbidden region for one or more atom of a bound conformation of a ligand. A forbidden region can be identified by overlaying two conformer models in a coordinate system and identifying a coordinate or set of coordinates differentially occupied by one or more atoms of the conformer models. A pharmacophore model incorporating a forbidden region as such will be specific for a polypeptide of one pharmacofamily over a polypeptide of a second pharmacofamily correspondent with the constraint incorporated.  
     [0134] An advantage of the invention is that a pharmacophore model can be created based on multiple structures of the same ligand. In comparison to a pharmacophore model derived from a single structure or different ligands, a pharmacophore model derived from multiple bound conformations of the same ligand can include a greater degree of geometric information. For example, averaging of multiple bound conformations of the same ligand can provide torsion angle constraints that are not available from a single structure and not evident from comparing different ligands.  
     [0135] The invention further provides a method for identifying a binding compound for one or more members of a polypeptide pharmacofamily by identifying a compound having a selected conformation-dependent property of a pharmacocluster. A binding compound can be any molecule having selected conformation-dependent properties of a ligand such that the binding compound can form a complex with one or more members of one or more polypeptide pharmacofamily. A method for identifying a binding compound for one or more members of a polypeptide pharmacofamily can include the steps of contacting a ligand with a polypeptide member of a pharmacofamily; identifying a conformation-dependent property associated with a bound conformation of the ligand bound to the polypeptide; comparing the conformation-dependent property of the bound conformation of the ligand bound to the polypeptide with a conformation-dependent property of a bound conformation of a ligand bound to another polypeptide in the same pharmacofamily; and identifying a ligand bound to the polypeptide with a conformation-dependent property similar to a bound conformation of a ligand bound to another polypeptide in the same pharmacofamily, thereby identifying a compound that binds one or more polypeptide members of a pharmacofamily. A compound that binds to one or more members of a polypeptide pharmacofamily can be identified by determining a conformation-dependent property by any of the methods described herein. For example, a ligand conformation or spectroscopic signal can provide a conformation-dependent property useful in identifying a compound that binds to one or more members of a polypeptide pharmacofamily.  
     [0136] The methods described herein for identifying a binding compound for one or more members of a polypeptide pharmacofamily can readily be adapted to a high throughput screening method. For example, methods of rapidly detecting a conformation-dependent property in a sequence of samples or detecting a conformation-dependent property in parallel samples can be applied to a high-throughput screen. One skilled in the art will know how to adapt the methods described here to a high throughput screening format using, for example, robotic manipulation of samples.  
     [0137] A method for identifying a binding compound for one or more members of a polypeptide pharmacofamily can include the steps of determining a bound conformation of a ligand bound to a polypeptide member of a polypeptide pharmacofamily; comparing the bound conformation of the ligand bound to the polypeptide member of the polypeptide pharmacofamily to a pharmacophore model; and identifying the bound conformation of the ligand bound to the polypeptide member of the polypeptide pharmacofamily that satisfies the constraints of the pharmacophore model as a binding compound for one or more members of the pharmacofamily in which the polypeptide member belongs.  
     [0138] A pharmacophore model can be useful in querying a database of polypeptide structures to find other members of a polypeptide pharmacofamily. For example, a member of a polypeptide pharmacofamily can be identified by querying a database of bound conformations of a ligand to retrieve a structure that fits the constraints of the query pharmacophore model, thereby identifying the retrieved polypeptide as a member of the pharmacofamily from which the pharmacophore model was derived. A pharmacophore model can also be used to identify a new member of a polypeptide pharmacofamily by querying a database of one or more polypeptide structures using an algorithm that docks or compares the pharmacophore model to polypeptide structures, wherein a favorable docking or comparison identifies a polypeptide as a member of the same polypeptide pharmacofamily from which the pharmacophore model was derived. The database queries described above can be performed with algorithms available in the art including, for example, THREEDOM and CATALYST.  
     [0139] An advantage of the invention is that a pharmacophore model can also be used to identify a binding compound that is specific for polypeptides of one or more pharmacofamilies. For example, a pharmacophore model can be compared to a structure of a compound or to a bound conformation of a ligand to identify those having similar properties. A conformer model can be further used to query a database of compounds to identify individual compounds having similar properties.  
     [0140] A pharmacophore model of the invention can also be used to design a binding compound that is specific for polypeptides of one or more pharmacofamilies. A pharmacophore model identified by these criteria can be used as a scaffold or set of constraints for developing a compound having enhanced binding affinity or specificity for polypeptides of of one or more pharmacofamilies. Using similar methods a pharmacophore model can be used to design a combinatorial synthesis producing a library of compounds having properties consistent or similar to the model which can be then be screened for enhanced binding affinity or specificity for polypeptide members of one or more pharmacofamilies. An algorithm can be used to design a binding compound based on a pharmacophore model including, for example, LUDI as described by Bohm,  J. Comput. Aided Mol. Des.  6:61-78 (1992).  
     [0141] A compound can be identified as satisfying the constraints of a pharmacophore model by a variety of methods for comparing structures. For example, a pharmacophore model that is a geometric representation such as a conformer model can be overlaid with a compound, and the best fit determined as described herein. Substantial overlap between a compound and a pharmacophore model can be indicated by a visual comparison and/or computation based comparison based on for example, RMSD values or torsion angle values as described above. In a case where a pharmacophore model is represented by constraints, a compound can be fitted to the pharmacophore model to identify if the properties of the compound satisfy the constraints of the pharmacophore model. For example, if a pharmacophore model contains, as a constraint, a maximum distance between atoms, a compound that satisfies the constraint can be identified as having a bond distance between corresponding atoms that is at least the maximum value. One skilled in the art will know how to extend such methods of comparison to any physical or chemical constraint.  
     [0142] A compound can also be identified as satisfying the constraints of a pharmacophore model by demonstrating the same characteristics for one or more specific atom located within a volume of space defined by the geometric constraints of the pharmacophore model. For example, in a case where polarity is a constraint and where a conformation of a compound can be overlaid with a pharmacophore model, an atom that overlaps a volume of space indicated by the pharmacophore and having polarity within the defined limits can be identified as satisfying constraints of the pharmacophore. By extension, a compound having atoms which satisfy all constraints of a pharmacophore is identified as a binding compound for one or more members of a polypeptide pharmacofamily from which the pharmacophore was produced.  
     [0143] Therefore, the invention provides a binding compound identified by the above described methods. For example, the invention provides a binding compound identified using a pharmacophore model or a conformer model derived from a pharmacocluster and/or pharmacofamily.  
     [0144] The invention provides a pharmacophore model, selected from the group consisting of pharmacophore model 1 having coordinates listed in Tables 3B and 3C, pharmacophore model 2 having coordinates listed in Tables 4B and 4C, pharmacophore model 3 having coordinates listed in Tables 5B and 5C, pharmacophore model 4 having coordinates listed in Tables 6B and 6C, pharmacophore model 5 having coordinates listed in Tables 7B and 7C, pharmacophore model 6 having coordinates listed in Tables 8B and 8C, pharmacophore model 7 having coordinates listed in Tables 9B and 9C, and pharmacophore model 8 having coordinates listed in Tables 10B and 10C.  
     [0145] The invention also provides a medium comprising a storage medium and stored in the medium, atom coordinates selected from the atomic coordinates listed in Table 3B, 3C, 4B, 4C, 5B, 5C, 6B, 6C, 7B, 7C, 8B, 8C, 9B, 9C, 10B or 10C, or a subset thereof. In one embodiment the medium comprises a computer readable medium. The use of a computer apparatus is convenient since atomic coordinates can be conveniently stored and accessed for manipulation including, for example, docking to a polypeptide structure or comparison to coordinates for other bound conformations of a ligand. Exemplary methods for manipulating atomic coordinates are described above.  
     [0146] It is understood that a computer apparatus of the invention need not itself store atomic coordinates of the invention. The computer apparatus contains an algorithm for viewing a structure from the coordinates or otherwise manipulating the coordinates. By using various hardware, software and network combinations, the atomic coordinates can be manipulated in a variety of configurations. Such a separate medium can be another computer apparatus, a storage medium such as a floppy disk, Zip disk or a server such as a file-server, which can be accessed by a carrier wave such as an electromagnetic carrier wave. One skilled in the art will know or can readily determine appropriate hardware, software or network interfaces that allow interconnection of an invention computer apparatus.  
     [0147] The methods of the invention described herein can be performed in a computer apparatus using the atomic coordinates listed in Table 3B, 3C, 4B, 4C, 5B, 5C, 6B, 6C, 7B, 7C, 8B, 8C, 9B, 9C, 10B or 10C by adding the step of entering the coordinates or a subset of the coordinates to the computer apparatus that performs a method of the invention. One skilled in the art will know or can readily determine an algorithm instructing a computer apparatus to carry out the methods of the invention.  
     [0148] It is understood that modifications which do not substantially affect the activity of the various embodiments of this invention are also provided within the definition of the invention provided herein. Accordingly, the following examples are intended to illustrate but not limit the present invention.  
     EXAMPLE I  
     Identification of Polypeptide Pharmacofamilies Based on Bound Conformations of NAD(P)(H) Ligands  
     [0149] This example describes identification of ligand conformer groups and corresponding polypeptide pharmacofamilies based on bound conformations of NAD(P)(H) bound to polypeptide oxidoreductases.  
     [0150] The oxidoreductases form a family of polypeptides that bind NAD(H) and NADP(H). In order to identify pharmacofamilies within the family of oxidoreductases, bound conformations of NAD(P)(H) were determined by searching the protein databank. Bound conformations from 156 structures were clustered into separate pharmacoclusters, and pharmacofamilies were identified according to binding to bound conformations of NAD(P)(H) in separate pharmacoclusters.  
     [0151] Structure files containing polypeptides with bound NAD(P)(H) were identified from the protein databank by keyword searches using the database software. Keywords included “NAD,” “NADH,” “NADP,” “NADPH,” “oxidoreductase,” “dehydrogenase” and “reductase.” Cluster analysis was performed using the algorithm COMPARE (Chiron Corp, 1995; distributed by Quantum Chemistry program Exchange, Indianapolis Ind.) in combination with visual inspection. All clusters were visually inspected using Insight 98 for outliers that demonstrated poor overlay with the rest of the pharmacocluster as a whole. These outliers were compared against each other and existing pharmacoclusters to find other possible matches. Those that did not fit any family were removed. Comparison between bound conformations was made based on the RMSD equations supplied in COMPARE.  
     [0152] Eight pharmacoclusters were identified by this method, as shown in FIG. 1. Visual inspection of the clusters in FIG. 1 demonstrates that members within a cluster are substantially overlapped. Comparison between clusters demonstrates substantial differences. For example, the bound conformations in cluster 5 have an extended structure compared to the bound conformations in cluster 4, which form a horseshoe like shape. Other differences include, for example, a flip in the nicotinamide ring between cluster 1 and cluster 2 such that the nicotinamide ring is anti to the ribose in cluster 1 and syn to the ribose in cluster 2 and a change in torsion angle in the bonds connecting the adenine ribose to the adenine phosphate for the bound conformations of cluster 3 compared to those of cluster 2.  
     [0153] The dihedral angles for various bonds in the bound conformations of the NADP(H) ligand can be used to distinguish the pharmacoclusters. As shown in Table 1 (see FIG. 2 for atom and bond locations), although many dihedral angles are similar between two or more pharmacoclusters, each pharmacocluster can be distinguished from the others by comparison of the full set of dihedral angles. For example, pharmacoclusters 2 and 3 can be distinguished by comparison between the dihedral angles at O4′A-C4′A-C5′A-O5′A which are 154 degrees and −131 degrees respectively and by comparison between the dihedral angles at C5′A-O5′A-PA-O3 which are 105 degrees and 57 degrees respectively.  
               TABLE 1                          Diedral Angles for Pharmacoclusters                                                                                     PC1       PC2       PC3       PC4       PC5       PC6       PC7       PC8           Dihedral angle   Avg.   std   Avg.   std   Avg.   std   Avg.   std   Avg.   std   Avg.   std   Avg.   std   Avg.   std                                                                                         O4′A-C1′A-N9A-C8A   75   24   75   11   69   18   85   7   72   3   18   16   81   12   105   6       O4′A-C4′A-C5′A-O5′A   180   19   154   30   −131   99   −166   12   65   4   79   11   168   12   −84   38       C4′A-C5′A-O5′A-PA   138   86   137   15   121   93   −152   2   180   6   −156   9   150   21   −171   3       C5′A-O5′A-PA-O3   65   39   105   44   57   44   55   0   −71   6   −82   7   58   10   −34   10       O5′A-PA-O3-PN   97   61   42   77   74   24   115   20   121   30   139   17   75   12   −188   16       PA-O3-PN-O5′N   −143   72   −165   53   −136   29   −152   10   50   27   84   15   107   27   128   39       O3-PN-O5′N-C5′N   70   44   56   86   101   36   −64   22   −92   13   64   25   27   45   72   7       PN-O5′N-C5′N-C4′N   181   14   176   41   162   27   145   7   −112   26   139   15   −136   13   191   18       O5′N-C5′N-C4′N-O4′N   −73   46   −58   40   −54   26   −55   10   −60   4   65   10   −69   13   183   20       O4′N-C1′N-N1N-C2 N   −120   24   69   17   53   11   59   5   −132   6   −117   10   −178   16   −122   6       C1′A-C2′A-C3′A-C4′A   −25   10   −29   5   −29   10   −37   23   −30   8   42   6   −1   46   −33   3       C1′N-C2′N-C3′N-C4′N   −36   44   −35   6   −28   20   22   9   40   2   −39   5   17   38   −17   3                  
 
     [0154] A quantitative analysis of the results of clustering bound conformations of NAD(P)(H) is provided in Table 2. Table 2 shows RMSD values calculated from comparisons between each pharmacocluster&#39;s average coordinates. Average coordinates were determined from the pharmacocluster subsets listed in Tables 3 through 10 as described below.  
               TABLE 2                          RMSD between each Pharmacocluster&#39;s average coordinates                                                     1   2   3   4   5   6   7   8                                                             1       1.89   2.24   3.81   2.31   2.74   2.68   1.42       2           0.95   3.61   2.51   3.47   2.52   2.62       3               3.88   2.85   3.36   3.00   3.02       4                   5.22   4.67   4.54   3.71       5                       2.49   1.93   2.88       6                           2.30   2.53       7                               3.06       8                  
 
     [0155] Tables 3A, 4A, 5A, 6A, 7A, 8A, 9A and 10A show RMSD values for subsets of members of pharmacoclusters 1-8, respectively. The RMSD values for each member were calculated as comparisons to an average structure for the subsets shown in each table respectively. For each pharmacocluster a subset of the possible ligands that belong to each cluster were identified. Each subset was chosen to maximize the diversity of the family and to minimize over-representation of ligand conformations from enzymes that exist multiply in the PDB database. The goal of the subset selection was to fully represent characteristics from oxidoreductases belonging to a range of species and catalyzing a range of different reactions. For example, there exists over ten alcohol dehydrogenases in the PDB database; however, for purposes of this study, only three were chosen from three different species for use in the 3D overlay and the pharmacophore construction. Average coordinates for the above described pharmacocluster subsets were obtained by overlaying ligand structures in MSI InsightII using the overlay function. The three dimensional coordinates for each atom in each ligand were used to calculate an average position and a standard deviation for the pharmacofamily.  
     [0156] Comparison of the RMSD values in part A of Tables 3 through 10 with the RMSD values in Table 2 demonstrate that a member of a pharmacocluster can be identified as having a lower RMSD compared to an average conformation of the members in its pharmacocluster than the RMSD between each family&#39;s average coordinates. In some cases it can be beneficial to combine two or more methods of comparison. For example, as described above pharmacoclusters 2 and 3 which have a relatively low RMSD when compared to each other can be distinguished from each other by visual inspection and by comparison of dihedral angles at various bonds.  
     [0157] These results demonstrate that bound conformations of a ligand can be grouped into pharmacoclusters by methods of structure comparison. These results also demonstrate methods for distinguishing pharmacoclusters and members within pharmacoclusters.  
     EXAMPLE II  
     Correlation Between the Structure of Polypeptides and the Bound Conformations of NAD(P)(H)  
     [0158] This example describes a correlation between bound conformations of NAD(P)(H) and structural classification of polypeptides such that polypeptides of a pharmacofamily have similar protein fold.  
     [0159] Pharmacoclusters for conformations of NAD(P)(H) bound to oxidoreductase polypeptides were clustered as described in Example I. For each polypeptide the protein fold, SCOP super-family designation and SCOP family designation was identified from the SCOP website administered by Laboratory of Molecular Biology at the MRC, Cambridge England (http://mrc-lmb.cam.ac.uk).  
     [0160] Table 11 shows the grouping of NAD(P)(H) binding polypeptides into 8 pharmacofamilies.  
               TABLE 11                          Pharmacofamilies                                     Polypeptide   Source   PDB   Fold   SCOP-Superfamily   SCOP-Family                         Family 1: NAD(P) Rossman Binding Domain (anti)                                     Alcohol Dehydrogenase   Horse   1a71   NAD(P) binding   NAD(P) binding   Alcohol/glucose           Liver       Rossman   Rossman   dehydrog.       Alcohol Dehydrogenase   human   1agn   NAD(P) binding   NAD(P) binding   Alcohol/glucose                   Rossman   Rossman   dehydrog.       Alcohol Dehydrogenase   Human   1dlt   NAD(P) binding   NAD(P) binding   Alcohol/glucose                   Rossman   Rossman   dehydrog.       Alcohol Dehydrogenase   Horse   1axe   NAD(P) binding   NAD(P) binding   Alcohol/glucose           Liver       Rossman   Rossman   dehydrog.       Alcohol Dehydrogenase   Horse   1axg   NAD(P) binding   NAD(P) binding   Alcohol/glucose           Liver       Rossman   Rossman   dehydrog.       Alcohol Dehydrogenase   cod fish   1cdo   NAD(P) binding   NAD(P) binding   Alcohol/glucose                   Rossman   Rossman   dehydrog.       Alcohol Dehydrogenase   Horse   1deh   NAD(P) binding   NAD(P) binding   Alcohol/glucose           Liver       Rossman   Rossman   dehydrog.       Alcohol Dehydrogenase   Human   1dls   NAD(P) binding   NAD(P) binding   Alcohol/glucose                   Rossman   Rossman   dehydrog.       Alcohol Dehydrogenase   human   1hdx   NAD(P) binding   NAD(P) binding   Alcohol/glucose                   Rossman   Rossman   dehydrog.       Alcohol Dehydrogenase   human   1hdy   NAD(P) binding   NAD(P) binding   Alcohol/glucose                   Rossman   Rossman   dehydrog.       Alcohol Dehydrogenase   Horse   1hdz   NAD(P) binding   NAD(P) binding   Alcohol/glucose           Liver       Rossman   Rossman   dehydrog.       Alcohol Dehydrogenase   Horse   1hld   NAD(P) binding   NAD(P) binding   Alcohol/glucose           Liver       Rossman   Rossman   dehydrog.       Alcohol Dehydrogenase   human   1htb   NAD(P) binding   NAD(P) binding   Alcohol/glucose                   Rossman   Rossman   dehydrog.       Alcohol Dehydrogenase   Cod   1kev   NAD(P) binding   NAD(P) binding   Alcohol/glucose           liver       Rossman   Rossman   dehydrog.       Alcohol Dehydrogenase   Horse   1lde   NAD(P) binding   NAD(P) binding   Alcohol/glucose           Liver       Rossman   Rossman   dehydrog.       Alcohol Dehydrogenase   horse   1ldy   NAD(P) binding   NAD(P) binding   Alcohol/glucose           liver       Rossman   Rossman   dehydrog.       Alcohol Dehydrogenase   human   1teh   NAD(P) binding   NAD(P) binding   Alcohol/glucose                   Rossman   Rossman   dehydrog.       Alcohol Dehydrogenase   Thermoan   1ykf   NAD(P) binding   NAD(P) binding   Alcohol/glucose           aerobium       Rossman   Rossman   dehydrog.       Alcohol Dehydrogenase   Horse   2ohx   NAD(P) binding   NAD(P) binding   Alcohol/glucose           Liver       Rossman   Rossman   dehydrog.       Alcohol Dehydrogenase   Horse   2oxi   NAD(P) binding   NAD(P) binding   Alcohol/glucose           Liver       Rossman   Rossman   dehydrog.       Alcohol Dehydrogenase   Horse   3bto   NAD(P) binding   NAD(P) binding   Alcohol/glucose           Liver       Rossman   Rossman   dehydrog.       Alcohol Dehydrogenase   human   3hud   NAD(P) binding   NAD(P) binding   Alcohol/glucose                   Rossman   Rossman   dehydrog.       D-2-hydroxyisocaproate   Lactobacillus   1dxy   NAD(P) binding   NAD(P) binding   Formate/glycerate       Dehydrogenase   Casei       Rossman   Rossman   dehydrog.       D-3-Phosphoglycerate     E. Coli     1psd   NAD(P) binding   NAD(P) binding   Formate/glycerate       Dehdrogenase           Rossman   Rossman   dehydrog.       Dihydrodipicolinate     E. Coli     1arz   NAD(P) binding   NAD(P) binding   Glyceraldehyde-3-       Reductase           Rossman   Rossman   phosphate                           dehydrog.       Dihydrodipicolinate     E. Coli     1dih   NAD(P) binding   NAD(P) binding   Glyceraldehyde-3-       Reductase           Rossman   Rossman   phosphate                           dehydrog.       Formate Dehydrogenase     Pyrobaculum     1qp8   NAD(P) binding   NAD(P) binding   Formate/glycerate             Aerophilum         Rossman   Rossman   dehydrog.       Formate Dehydrogenase     Methylotrophic     2nad   NAD(P) binding   NAD(P) binding   Formate/glycerate             Pseudomonas         Rossman   Rossman   dehydrog.       L-2-hydroxyisocaproate     Lactobacillus     1hyh   NAD(P) binding   NAD(P) binding   Formate/glycerate       dehydrogenase     Confusus         Rossman   Rossman   dehydrog.       L-Alanine     Phormidium     1pjc   NAD(P) binding   NAD(P) binding   Formate/glycerate       Dehydrogenase     Lapideum         Rossman   Rossman   dehydrog.       L-Lactate     Plasmodium     1ldg   NAD(P) binding   NAD(P) binding   Lactate &amp; malate       Dehydrogenase     Falciparum         Rossman   Rossman   dehydrog. (N-                           term)       L-Lactate     Bacillus     1ldl   NAD(P) binding   NAD(P) binding   Lactate &amp; malate       Dehydrogenase     Delbreuckii         Rossman   Rossman   dehydrog. (N-                           term)       L-Lactate     B. Steariothermophilus     1ldn   NAD(P) binding   NAD(P) binding   Lactate &amp; malate       Dehydrogenase           Rossman   Rossman   dehydrog. (N-                           term)       L-Lactate     Bifidobacterium     1lld   NAD(P) binding   NAD(P) binding   Lactate &amp; malate       Dehydrogenase     Longum         Rossman   Rossman   dehydrog. (N-                           term)       L-Lactate     Bifidobacterium     1lth   NAD(P) binding   NAD(P) binding   Lactate &amp; malate       Dehydrogenase     Longum         Rossman   Rossman   dehydrog. (N-                           term)       L-Lactate     B. Steariothermophilus     2ldb   NAD(P) binding   NAD(P) binding   Lactate &amp; malate       Dehydrogenase           Rossman   Rossman   dehydrog. (N-                           term)       L-Lactate   Pig   9ldb   NAD(P) binding   NAD(P) binding   Lactate &amp; malate       Dehydrogenase   Muscle       Rossman   Rossman   dehydrog. (N-                           term)       L-Lactate   Pig   9ldt   NAD(P) binding   NAD(P) binding   Lactate &amp; malate       Dehydrogenase   Muscle       Rossman   Rossman   dehydrog. (N-                           term)       Malate Dehydrogenase     Aquaspirillum     1b8u   NAD(P) binding   NAD(P) binding   Lactate &amp; malate             Arcticum         Rossman   Rossman   dehydrog. (N-                           term)       Malate Dehydrogenase     Thermus     1bmd   NAD(P) binding   NAD(P) binding   Lactate &amp; malate             Flavis         Rossman   Rossman   dehydrog. (N-                           term)       Malate Dehydrogenase     E. Coli     1cme   NAD(P) binding   NAD(P) binding   Lactate &amp; malate                   Rossman   Rossman   dehydrog. (N-                           term)       Malate Dehydrogenase     E. Coli     1emd   NAD(P) binding   NAD(P) binding   Lactate &amp; malate                   Rossman   Rossman   dehydrog. (N-                           term)       Malate Dehydrogenase     Haloarcula     1hlp   NAD(P) binding   NAD(P) binding   Lactate &amp; malate             Marismortui         Rossman   Rossman   dehydrog. (N-                           term)       Malate Dehydrogenase   Pig   4mdh   NAD(P) binding   NAD(P) binding   Lactate &amp; malate           Heart       Rossman   Rossman   dehydrog. (N-                           term)       Malate Dehydrogenase   Pig   5mdh   NAD(P) binding   NAD(P) binding   Lactate &amp; malate           Heart       Rossman   Rossman   dehydrog. (N-                           term)       Malic Enzyme   human   1qr6   NAD(P) binding   NAD(P) binding   Amino-acid                   Rossman   Rossman   dehydrog (C-term)       S-AdenosylHomocysteine   Rat   1b3r   NAD(P) binding   NAD(P) binding   Formate/glycerate       Hydrolase           Rossman   Rossman   dehydrog.       Tetrahydrofolate   Human   1a4i   NAD(P) binding   NAD(P) binding   Amino-acid       Dehydrogenase           Rossman   Rossman   dehydrog (C-term)                 Family 2: NAD(P) Rossman Binding Domain (Syn)                                     Glutamate   Bovine   1ch6   NAD(P) binding   NAD(P) binding   Amino-acid       Dehydrogenase   Liver       Rossman   Rossman   dehydrog (C-term)       Glyceraldehyde-3-     Leishmania     1a7k   NAD(P) binding   NAD(P) binding   Glyceraldehydes-3-       phosphate     Mexicana         Rossman   Rossman   phosphate       Dehydrogenase                   dehydrog. (N-term)       Glyceraldehyde-3-     Thermus     1cer   NAD(P) binding   NAD(P) binding   Glyceraldehydes-3-       phosphate     aquaticus         Rossman   Rossman   phosphate       Dehydrogenase                   dehydrog. (N-term)       Glyceraldehyde-3-     B. Stearothermophilus     1dbv   NAD(P) binding   NAD(P) binding   Glyceraldehydes-3-       phosphate           Rossman   Rossman   phosphate       Dehydrogenase                   dehydrog. (N-term)       Glyceraldehyde-3-     E. Coli     1gad   NAD(P) binding   NAD(P) binding   Glyceraldehydes-3-       phosphate           Rossman   Rossman   phosphate       Dehydrogenase                   dehydrog. (N-term)       Glyceraldehyde-3-     E. Coli     1gae   NAD(P) binding   NAD(P) binding   Glyceraldehydes-3-       phosphate           Rossman   Rossman   phosphate       Dehydrogenase                   dehydrog. (N-term)       Glyceraldehyde-3-     B. Stearothermophilus     1gd1   NAD(P) binding   NAD(P) binding   Glyceraldehydes-3-       phosphate           Rossman   Rossman   phosphate       Dehydrogenase                   dehydrog. (N-term)       Glyceraldehyde-3-   Trypanosoma   1gga   NAD(P) binding   NAD(P) binding   Glyceraldehydes-3-       phosphate   Brucei       Rossman   Rossman   phosphate       Dehydrogenase   Brucei               dehydrog. (N-term)       Glyceraldehyde-3-     Leishmania     1gyp   NAD(P) binding   NAD(P) binding   Glyceraldehydes-3-       phosphate     Mexicana         Rossman   Rossman   phosphate       Dehydrogenase                   dehydrog. (N-term)       Glyceraldehyde-3-     Thermatoga     1hdg   NAD(P) binding   NAD(P) binding   Glyceraldehydes-3-       phosphate     Marinata         Rossman   Rossman   phosphate       Dehydrogenase                   dehydrog. (N-term)       Glyceraldehyde-3-     Palinurus     1szj   NAD(P) binding   NAD(P) binding   Glyceraldehydes-3-       phosphate     Versicolor         Rossman   Rossman   phosphate       Dehydrogenase                   dehydrog. (N-term)       Glyceraldehyde-3-     B. Stearothermophilus     2dbv   NAD(P) binding   NAD(P) binding   Glyceraldehydes-3-       phosphate           Rossman   Rossman   phosphate       Dehydrogenase                   dehydrog. (N-term)       Glyceraldehyde-3-     B. Stearothermophilus     3dbv   NAD(P) binding   NAD(P) binding   Glyceraldehydes-3-       phosphate           Rossman   Rossman   phosphate       Dehydrogenase                   dehydrog. (N-term)       L-3-Hydroxyacyl COA   Human   2hdh   NAD(P) binding   NAD(P) binding   6-       Dehydrogenase   Heart       Rossman   Rossman   phosphogluconate       Dehdrogenase                   dehydrog. (N-                           term)       Phenylalanine   Rhodococcus   1bxg   NAD(P) binding   NAD(P) binding   Amino-acid       Dehydrogenase   Sp.       Rossman   Rossman   dehydrog (C-term)                 Family 3: NAD(P) Rossman Binding Domain (Syn) Tyrosine Depependent Oxidoreductases                                     17β-Hydroxysteroid   Human   1a27   NAD(P) binding   NAD(P) binding   Tyrosine-       Dehydrogenase           Rossman   Rossman   dependent       2α-20β-Hydroxysteroid   Strep.   2hsd   NAD(P) binding   NAD(P) binding   Tyrosine-       Dehydrogenase   Hydrogenans       Rossman   Rossman   dependent       7α-Hydroxysteroid     E. Coli     1ahh   NAD(P) binding   NAD(P) binding   Tyrosine-       Dehydrogenase           Rossman   Rossman   dependent       7α-Hydroxysteroid     E. Coli     1ahi   NAD(P) binding   NAD(P) binding   Tyrosine-       Dehydrogenase           Rossman   Rossman   dependent       7α-Hydroxysteroid     E. Coli     1fmc   NAD(P) binding   NAD(P) binding   Tyrosine-       Dehydrogenase           Rossman   Rossman   dependent       Carbonyl Reductase   Mouse   1cyd   NAD(P) binding   NAD(P) binding   Tyrosine-                   Rossman   Rossman   dependent       Cis-Biphenyl-2,3-   Pseudomonas   1bdb   NAD(P) binding   NAD(P) binding   Tyrosine-       Dihydrodiol-2,3-   sp.       Rossman   Rossman   dependent       Dehydrogenase       Dihydropteridine   Rat   1dir   NAD(P) binding   NAD(P) binding   Tyrosine-       Reductase   Liver       Rossman   Rossman   dependent       Dihydropteridine   Human   1hdr   NAD(P) binding   NAD(P) binding   Tyrosine-       Reductase           Rossman   Rossman   dependent       Enoyl Acyl Carrier     M.     1bvr   NAD(P) binding   NAD(P) binding   Tyrosine-       Protein Reductase     Tuberculosis         Rossman   Rossman   dependent       Enoyl Acyl Carrier     Brassica     1cwu   NAD(P) binding   NAD(P) binding   Tyrosine-       Protein Reductase     Napus  (rape)       Rossman   Rossman   dependent       Enoyl Acyl Carrier     E. Coli     1dfg   NAD(P) binding   NAD(P) binding   Tyrosine-       Protein Reductase           Rossman   Rossman   dependent       Enoyl Acyl Carrier     E. Coli     1dfh   NAD(P) binding   NAD(P) binding   Tyrosine-       Protein Reductase           Rossman   Rossman   dependent       Enoyl Acyl Carrier     E. Coli     1dfi   NAD(P) binding   NAD(P) binding   Tyrosine-       Protein Reductase           Rossman   Rossman   dependent       Enoyl Acyl Carrier     Myobacterium     1eny   NAD(P) binding   NAD(P) binding   Tyrosine-       Protein Reductase     Tuberculosis         Rossman   Rossman   dependent       Enoyl Acyl Carrier     Mybacterium     1enz   NAD(P) binding   NAD(P) binding   Tyrosine-       Protein Reductase     Tuberculosis         Rossman   Rossman   dependent       Enoyl Acyl Carrier     E. Coli     1qg6   NAD(P) binding   NAD(P) binding   Tyrosine-       Protein Reductase           Rossman   Rossman   dependent       Enoyl Acyl Carrier   Common   1qsg   NAD(P) binding   NAD(P) binding   Tyrosine-       Protein Reductase   Bacteria       Rossman   Rossman   dependent       GDP-Fucose Synthase     E. Coli     1bsv   NAD(P) binding   NAD(P) binding   Tyrosine-                   Rossman   Rossman   dependent       Sepiapterin Reductase     E. Coli     1nas   NAD(P) binding   NAD(P) binding   Tyrosine-                   Rossman   Rossman   dependent       Sepiapterin Reductase   mouse   1sep   NAD(P) binding   NAD(P) binding   Tyrosine-                   Rossman   Rossman   dependent       Trihydroxynaphthalene   Rice   1ybv   NAD(P) binding   NAD(P) binding   Tyrosine-       Reductase   Fungus       Rossman   Rossman   dependent       Tropinone Reductase-I   Jimson   1ae1   NAD(P) binding   NAD(P) binding   Tyrosine-           Weed       Rossman   Rossman   dependent       Tropinone Reductase-II   Jimsonweed   2ae2   NAD(P) binding   NAD(P) binding   Tyrosine-                   Rossman   Rossman   dependent       UDP-Galactose     E. Coli     1a9y   NAD(P) binding   NAD(P) binding   Tyrosine-       Epimerase           Rossman   Rossman   dependent       UDP-Galactose     E. Coli     1a9z   NAD(P) binding   NAD(P) binding   Tyrosine-       Epimerase           Rossman   Rossman   dependent       UDP-Galactose     E. Coli     1kvq   NAD(P) binding   NAD(P) binding   Tyrosine-       Epimerase           Rossman   Rossman   dependent       UDP-Galactose     E. Coli     1kvr   NAD(P) binding   NAD(P) binding   Tyrosine-       Epimerase           Rossman   Rossman   dependent       UDP-Galactose     E. Coli     1kvs   NAD(P) binding   NAD(P) binding   Tyrosine-       Epimerase           Rossman   Rossman   dependent       UDP-Galactose     E. Coli     1kvt   NAD(P) binding   NAD(P) binding   Tyrosine-       Epimerase           Rossman   Rossman   dependent       UDP-Galactose     E. Coli     1kvu   NAD(P) binding   NAD(P) binding   Tyrosine-       Epimerase           Rossman   Rossman   dependent       UDP-Galactose     E. Coli     1nai   NAD(P) binding   NAD(P) binding   Tyrosine-       Epimerase           Rossman   Rossman   dependent       UDP-Galactose     E. Coli     1uda   NAD(P) binding   NAD(P) binding   Tyrosine-       Epimerase           Rossman   Rossman   dependent       UDP-Galactose     E. Coli     1udb   NAD(P) binding   NAD(P) binding   Tyrosine-       Epimerase           Rossman   Rossman   dependent       UDP-Galactose     E. Coli     1udc   NAD(P) binding   NAD(P) binding   Tyrosine-       Epimerase           Rossman   Rossman   dependent       UDP-Galactose     E. Coli     1xel   NAD(P) binding   NAD(P) binding   Tyrosine-       Epimerase           Rossman   Rossman   dependent       3α, 20 β-   Strep.   2hsd   NAD(P) binding   NAD(P) binding   Tyrosine-       hydroxysteroid   Hydrogenas       Rossman   Rossman   dependent       dehydrogenase       17-β hydroxy steroid   Human   1fdu   NAD(P) binding   NAD(P) binding   Tyrosine-       Dehydr.           Rossman   Rossman   dependent       17-β hydroxy steroid   Human   1fdv   NAD(P) binding   NAD(P) binding   Tyrosine-       Dehydr.           Rossman   Rossman   dependent                 Family 4: Catalases                                     Catalase   Proteus   2cah   Heme linked   Heme linked   Heme linked           Mirabilis       catalase   catalase   catalase       Catalase   cow   7cat   Heme linked   Heme linked   Heme linked           Liver       catalase   catalase   catalase       Catalase   cow   8cat   Heme linked   Heme linked   Heme linked           Liver       catalase   catalase   catalase                 Family 5: β-α TIM Barrel                                     2,5-Diketo-D-Gluconic   Cornybacterium   1a80   β-α TIM Barrel   NAD(P)-linkded   Aldo-keto       Acid Reductase   sp.           Oxidoreductase   Reductase       3-α-hydroxysteroid   Rat   1afs   β-α TIM Barrel   NAD(P)-linkded   Aldo-keto       Dehydrogenase               Oxidoreductase   Reductase       Aldehyde Reductase   Pig   1ae4   β-α TIM Barrel   NAD(P)-linkded   Aldo-keto                       Oxidoreductase   Reductase       Aldehyde Reductase   Pig   1cwn   β-α TIM Barrel   NAD(P)-linkded   Aldo-keto                       Oxidoreductase   Reductase       Aldo-keto Reductase   Mouse   1frb   β-α TIM Barrel   NAD(P)-linkded   Aldo-keto                       Oxidoreductase   Reductase       Aldose Reductase   Human   1abn   β-α TIM Barrel   NAD(P)-linkded   Aldo-keto                       Oxidoreductase   Reductase       Aldose Reductase   Human   1ads   β-α TIM Barrel   NAD(P)-linkded   Aldo-keto                       Oxidoreductase   Reductase       Aldose Reductase   Pig   1ah0   β-α TIM Barrel   NAD(P)-linkded   Aldo-keto                       Oxidoreductase   Reductase       Aldose Reductase   Pig eye   1ah3   β-α TIM Barrel   NAD(P)-linkded   Aldo-keto                       Oxidoreductase   Reductase       Aldose Reductase   Pig   1ah4   β-α TIM Barrel   NAD(P)-linkded   Aldo-keto                       Oxidoreductase   Reductase       Aldose Reductase   Human   1az1   β-α TIM Barrel   NAD(P)-linkded   Aldo-keto                       Oxidoreductase   Reductase       Aldose Reductase   Human   1az2   β-α TIM Barrel   NAD(P)-linkded   Aldo-keto                       Oxidoreductase   Reductase       Aldose Reductase   Human   1mar   β-α TIM Barrel   NAD(P)-linkded   Aldo-keto                       Oxidoreductase   Reductase       Aldose Reductase   Human   2acq   β-α TIM Barrel   NAD(P)-linkded   Aldo-keto                       Oxidoreductase   Reductase       Aldose Reductase   Human   2acr   β-α TIM Barrel   NAD(P)-linkded   Aldo-keto                       Oxidoreductase   Reductase       Aldose Reductase   Human   2acs   β-α TIM Barrel   NAD(P)-linkded   Aldo-keto                       Oxidoreductase   Reductase       Aldose Reductase   Human   2acu   β-α TIM Barrel   NAD(P)-linkded   Aldo-keto                       Oxidoreductase   Reductase                 Family 6: Dihydrofolate Reductases                                     Dihydrofolate     Candida     1ai9   Dihydrofolate   Dihydrofolate   Dihydrofolate       Reductase     Albicans         Reductase   Reductase   Reductase       Dihydrofolate     Candida     1aoe   Dihydrofolate   Dihydrofolate   Dihydrofolate       Reductase     Albicans         Reductase   Reductase   Reductase       Dihydrofolate   Pneumocystis   1daj   Dihydrofolate   Dihydrofolate   Dihydrofolate       Reductase   carinii       Reductase   Reductase   Reductase       Dihydrofolate   Human   1dlr   Dihydrofolate   Dihydrofolate   Dihydrofolate       Reductase           Reductase   Reductase   Reductase       Dihydrofolate   Human   1dls   Dihydrofolate   Dihydrofolate   Dihydrofolate       Reductase           Reductase   Reductase   Reductase       Dihydrofolate   Chicken   1dr1   Dihydrofolate   Dihydrofolate   Dihydrofolate       Reductase   Liver       Reductase   Reductase   Reductase       Dihydrofolate   Chicken   1dr4   Dihydrofolate   Dihydrofolate   Dihydrofolate       Reductase   Liver       Reductase   Reductase   Reductase       Dihydrofolate   Chicken   1dr5   Dihydrofolate   Dihydrofolate   Dihydrofolate       Reductase   Liver       Reductase   Reductase   Reductase       Dihydrofolate   Chicken   1dr6   Dihydrofolate   Dihydrofolate   Dihydrofolate       Reductase   Liver       Reductase   Reductase   Reductase       Dihydrofolate   Chicken   1dr7   Dihydrofolate   Dihydrofolate   Dihydrofolate       Reductase   Liver       Reductase   Reductase   Reductase       Dihydrofolate     E. Coli     1dre   Dihydrofolate   Dihydrofolate   Dihydrofolate       Reductase           Reductase   Reductase   Reductase       Dihydrofolate     E. Coli     1drh   Dihydrofolate   Dihydrofolate   Dihydrofolate       Reductase           Reductase   Reductase   Reductase       Dihydrofolate   Pneumocystis   1dyr   Dihydrofolate   Dihydrofolate   Dihydrofolate       Reductase   carinii       Reductase   Reductase   Reductase       Dihydrofolate   Human   1hfp   Dihydrofolate   Dihydrofolate   Dihydrofolate       Reductase           Reductase   Reductase   Reductase       Dihydrofolate   Human   1hfq   Dihydrofolate   Dihydrofolate   Dihydrofolate       Reductase           Reductase   Reductase   Reductase       Dihydrofolate   Human   1hfr   Dihydrofolate   Dihydrofolate   Dihydrofolate       Reductase           Reductase   Reductase   Reductase       Dihydrofolate   Human   1ohj   Dihydrofolate   Dihydrofolate   Dihydrofolate       Reductase           Reductase   Reductase   Reductase       Dihydrofolate   Human   1ohk   Dihydrofolate   Dihydrofolate   Dihydrofolate       Reductase           Reductase   Reductase   Reductase       Dihydrofolate     E. Coli     1ra2   Dihydrofolate   Dihydrofolate   Dihydrofolate       Reductase           Reductase   Reductase   Reductase       Dihydrofolate     E. Coli     1rb2   Dihydrofolate   Dihydrofolate   Dihydrofolate       Reductase           Reductase   Reductase   Reductase       Dihydrofolate     E. Coli     1rh3   Dihydrofolate   Dihydrofolate   Dihydrofolate       Reductase           Reductase   Reductase   Reductase       Dihydrofolate     E. Coli     1rx1   Dihydrofolate   Dihydrofolate   Dihydrofolate       Reductase           Reductase   Reductase   Reductase       Dihydrofolate     E. Coli     1rx2   Dihydrofolate   Dihydrofolate   Dihydrofolate       Reductase           Reductase   Reductase   Reductase       Dihydrofolate     E. Coli     1rx3   Dihydrofolate   Dihydrofolate   Dihydrofolate       Reductase           Reductase   Reductase   Reductase       Dihydrofolate   Lactobacillus   3dfr   Dihydrofolate   Dihydrofolate   Dihydrofolate       Reductase   casei       Reductase   Reductase   Reductase       Dihydrofolate     E. Coli     7dfr   Dihydrofolate   Dihydrofolate   Dihydrofolate       Reductase           Reductase   Reductase   Reductase       Dihydrofolate   Chicken   8dfr   Dihydrofolate   Dihydrofolate   Dihydrofolate       Reductase   Liver       Reductase   Reductase   Reductase                 Family 7: FAD/NAD(P) Binding Oxidoreductases (‘Disulfide Oxidoreductases’)                                     Glutathione Reductase   E.Coli   1get   FAD/NAD(P)   FAD/NAD(P)   FAD/NAD-linked                   Binding Domain   Binding Domain   reductases       Glutathione Reductase   E.Coli   1geu   FAD/NAD(P)   FAD/NAD(P)   FAD/NAD-linked                   Binding Domain   Binding Domain   reductases       Glutathione Reductase   Human   1grb   FAD/NAD(P)   FAD/NAD(P)   FAD/NAD-linked                   Binding Domain   Binding Domain   reductases       NADH Peroxidase     Streptococcus     2npx   FAD/NAD(P)   FAD/NAD(P)   FAD/NAD-linked             Faecalis         Binding Domain   Binding Domain   reductases       Thioredoxin Reductase     E. Coli     1tdf   FAD/NAD(P)   FAD/NAD(P)   FAD/NAD-linked                   Binding Domain   Binding Domain   reductases       Trypanothione     Crithidia     1typ   FAD/NAD(P)   FAD/NAD(P)   FAD/NAD-linked       Reductase* (by active     Fasciculata         Binding Domain   Binding Domain   reductases       site)                 Family 8: Ferrodoxin-like                                     Ferrodoxin Reductase   Pea   1qga   Ferrodoxin like   Ferrodoxin like   Reductases       P450 Reductase   Rat   —   Ferrodoxin like   Ferrodoxin like   NADPH-cytochrome                           P450 reductase                  
 
     [0161] The results shown in Table 11 demonstrate that bound conformation of NAD(P)(H) can be correlated with protein fold. Grouping oxidoreductases into pharmacofamilies based on the bound conformations of NAD(P)(H) resulted in a correlation with protein fold. Pharmacofamilies 1-3 consist of polypeptides having the NAD(P)(H) binding Rossman fold. Pharmacofamily 4 consists of polypeptides having heme-linked catalase fold. Pharmacofamily 5 consists of polypeptides having the β-α TIM barrel fold. Pharmacofamily 6 consists of polypeptides having the dihydrofolate reductase fold. Pharmacofamily 7 consists of polypeptides having the FAD/NAD(P)(H) binding domain fold. Trypanathione reductase was added to family 7 by homology of its active site to the active sites of other members of pharmacofamily 7 independent of bound ligand conformation. Pharmacofamily 8 consists of polypeptides having the ferrodoxin like fold. Pharmacofamilies 1 and 2 were identified based on anti or syn conformation, respectively, of the nicotinamide ring relative to the ribose. Additionally, a change in the torsion angles in the bonds connecting the adenine ribose to the adenine phosphate separates the family members having a Rossman fold into a third pharmacofamily, identified as pharmacofamily 3.  
     [0162] The results described in this example demonstrate that a bound conformation of a ligand can be correlated with polypeptide fold. Furthermore, the results obtained by the method are consistent with results obtained by SCOP. Therefore, classification based on bound conformation of ligands can be used to classify polypeptides according to structure.  
     EXAMPLE III  
     Determination of a Conformer Model and Pharmacophore for Pharmacoclusters 1-8  
     [0163] This example demonstrates determination of the average bound conformations from pharmacoclusters 1-8 and construction of conformer models based on the average bound conformations. This example also demonstrates construction of a pharmacophore model based on the average bound conformations and interactions with polypeptides.  
     [0164] Conformer models for each pharmacocluster were produced by determining an average structure for the subset of members of each pharmacocluster as described in Example I. The coordinates for conformer models of pharmacoclusters 1-8 are shown in Part C of Tables 3-10 respectively.  
     [0165] Pharmacophore models were constructed by aligning the active sites of a pharmacofamily of oxidoreductases. Three-dimensional overlays were achieved using Insight II overlay module to overlay the NAD(P) ligands of each enzyme-ligand complex. Heteroatoms in the surrounding protein that could function as hydrogen bond acceptors or hydrogen bond donors were identified in each complex that made interactions with the NAD(P) ligand. These heteroatoms that had common positions in three dimensional space (within 3 Å of each other in the overlay) in each enzyme complex and that made a common interaction with the ligand were then grouped together and tabulated for pharmacophore construction. Water molecules were similarly identified and grouped. The grouped heteroatoms and water molecules are listed in Part D of Tables 3-10 below. Finally the average coordinates and the standard deviation for each interaction group were calculated. The final pharmacophore model was produced by overlaying interaction groups on the conformer model (average ligand structure).  
     [0166] The coordinates for pharmacophore models of pharmacoclusters 1-8 are shown in parts B and C of Tables 3-10, respectively. Specifically, each conformer model includes the average NAD(P) coordinates (in part C of each Table) and the pharmacophore model includes both the average NADP coordinates, average water coordinates and the average protein heteroatom coordinates (including coordinates in both part B and C of each Table). An exception is the pharmacophore model derived from pharmacofamily 7 which includes average water coordinates and average protein heteroatom coordinates for all polypeptides listed but has a conformer model derived from NAD(P) bound to each polypeptide listed except trypanathione reductase.  
     [0167] A structural representation of each conformer model with overlayed interaction groups used to determine respective pharmacophore models 1-8 is provided in FIG. 3. The structures shown in FIG. 3 reflect the average NAD(P) coordinates shown in Part C of Tables 3-10 and the coordinates for all interacting groups used to calculate the average water coordinates and the average protein heteroatom coordinates as shown in Part D of Tables 3-10. Hydrogen bond acceptors are labeled with an ‘A’ followed by a number for each group. These are listed in the pharmacophore Tables and designated on the pharmacophore figures. Donors are labeled with a ‘D’; and water molecules are labeled with a ‘W’.  
     [0168] This example demonstrates construction of conformer models based on the bound conformations of ligands in pharmacoclusters. This example also demonstrates construction of a pharmacophore model based on the bound conformations of ligands in pharmacoclusters and their interactions with polypeptides in their respective pharmacofamilies.  
     EXAMPLE IV  
     Correlation Between the Bound Conformation of Ligands and a Conformation-Dependent Property  
     [0169] This example describes a conformation-dependent property that is correlated with a bound conformation of a ligand.  
     [0170] A 2D [ 1 H, 1 H] NOESY spectrum was recorded with a 0.2 ml sample of 1 mM NADP and 200 μM of enzyme 1-deoxy D-xylulose 5-phosphate reductoisomerase (DOXP). The spectrum was measured with a Bruker DRX700 spectrometer operating at 700 MHZ  1 H frequency. The total measuring time was about 12 h.  
     [0171] The spectrum is shown in FIG. 4 and atoms are identified according to FIG. 2. The relative intensities of the observed transferred NOEs (trNOEs) between the ribose proton H-C1′N(NC1′) and the protons on the nicotinamide ring, H-C4N and H-C2N shown in FIG. 4, reveal that the NADP adopts a syn conformation when bound to the enzyme.  
     [0172] The bound conformations in Pharmacocluster 1 and 2 can be distinguished according to anti or syn conformation, respectively, of the nicotinamide ring relative to the ribose. Therefore, these results demonstrate that the relative intensities of the observed trNOE&#39;s between the ribose proton H-C1′N(NC1′) and the protons on the nicotinamide ring, H-C4N and H-C2N can provide a conformation dependent property useful in distinguishing members of pharmacoclusters 1 and 2.  
     EXAMPLE V  
     Binding Compounds Having Specificity for One or More Polypeptide Pharmacofamilies  
     [0173] This example demonstrates querying a database of compounds to identify individual compounds having similar conformations. This example also demonstrates preferential binding of a compound to a polypeptide of one pharmacofamily over another.  
     [0174] The TTE0001.001.A07 AND TTE0001.002.D02 compounds were identified by using the THREEDOM algorithm to query a database of commercially available molecules (ASINEX; Moscow, Russia) by shape matching with cibacron blue. Coordinates of cibacron blue were obtained from the published 3D structure (Li et al.,  Proc. Natl. Acad. Sci. USA  92:8846-8850 (1995)). The database was created by converting an SD format file of structures from ASINEX to INTERCHEM format coordinates using the batch2to3 program. Cibacron blue was compared against each structure in the database in multiple orientations to generate a matching score. Out of 37,926 structures searched, the 750 best matching scores were selected. From these 750 structures, TTE0001.001.A07 AND TTE0001.002.D02 were selected and purchased based on objective criteria such as likely favorable binding interactions, pharmacophore properties, synthetic accessibility and likely pharmacokinetic, toxicological, adsorption and metabolic properties.  
     [0175] Kinetic studies were carried out in 1-cm cuvettes in a 1 mL volume at 25° C. Lactate dehydrogenase reactions were monitored spectrophotometrically with a Cary 300 by following the decrease in absorbance at 340 nm due to the oxidation of NADH by pyruvate. Lactate dehydrogenase reaction mixtures contained 100 mM Hepes buffer at pH 7.4, as well as 2.5 mM pyruvate, 10 μM NADH, 5 ng/mL lactate dehydrogenase. NADPH, NADH, Hepes buffer, and rabbit muscle lactate dehydrogenase were purchased from Sigma. Cytochrome P450 reductase reactions were monitored by following the decrease in absorbance at 550 nm due to the reduction of ferric cytochrome c by NADPH. Cytochrome P450 reductase reaction mixtures contained 100 mM Hepes buffer at pH 7.4, as well as 80 μM ferric cytochrome c, 10 μM NADPH, and 80 ng/mL cytochrome P450 reductase. Data were fitted using the FORTRAN programs of Cleland,  Adv. Enzymol.  45: 273-387 (1977) which perform nonlinear least squares fits to the appropriate equations. Substrates were varied around their Michaelis constants, while nonvaried substrate was kept at a concentration close to its Michaelis constant. The concentration of inhibitor that gives 50% inhibition (IC50) values were obtained by fitting data to the equation for a line, where Y values are 1/rate and X values are the concentration of inhibitor, as in a Dixon plot (Segel, supra). The X-intercept is the IC50. If a full kinetic profile was done, then K is  values were obtained by fitting the data to the equation for a competitive inhibitor:  
       rate   =         V   max        A           K   m          (     1   +     I   /     K     1      s           )       +   A                     
 
     [0176] where rate is the rate of reaction in units of absorbance/minute, V max is  the maximum velocity, K m  is the Michaelis constant for A, K is  is the inhibition dissociation constant for the inhibitor, I is the inhibitor concentration, and A is the concentration of NADH or NADPH. In all cases, the fit to the above equation was used only after establishing that the fit to equations for noncompetitive and uncompetitive inhibition were less appropriate based on values for sigma (overall fit) as well as standard deviations for fitted constants (K is  and K is .  
     [0177] As shown in FIG. 5, compound TTE0001.00.A07 could inhibit binding of NADH to lactate dehydrogenase and NADPH to cytochrome P450 reductase which are polypeptide members of pharmacofamily 1 and 8 respectively. Compound TTE0001.001.A07 demonstrated high binding affinity for both lactate dehydrogenase and cytochrome P450 reductase.  
     [0178] Analysis of inhibition of binding between NADH and lactate dehydrogenase is shown in FIG. 6. Compound TTE0001.002.D02 inhibited lactate dehydrogenase with a K 1 s of 2.1 μM. Similar measurements of cytochrome P450 reductase with concentrations of compound TTE0001.002.D02 up to 0.5 mM did not indicate inhibition. These results indicated that compound TTE0001.002.D02 had a K is  of greater than 1 mM with cytochrome P450 reductase. Thus, compound TTE0001.002.D02 demonstrated preferential binding for pharmacofamily 1 having an inhibitory dissociation constant (K is ) that was at least 500 fold lower than for pharmacofamily 8.  
     [0179] The results described in this example demonstrate that a binding compound can be identified by structural comparison to a bound conformation of a ligand. Furthermore, the results demonstrate that binding compounds that interact with polypeptides from multiple pharmacofamilies or compounds that preferentially bind to polypeptides of one pharmacofamily compared to polypetides of another pharmacofamily can be identified by structural comparison to a bound conformation of a ligand.  
     EXAMPLE VI  
     Identification of a Ligand Using a Pharmacophore Model  
     [0180] This example demonstrates construction of a pharmacophore model, use of the model to identify a binding ligand and confirmation of the ability of the identified compound to bind a polypeptide member of the pharmacofamily from which the pharmacophore model was derived.  
     [0181] Pharmacophore models were constructed to include part or all of the NAD(P) shape, hydrogen bond donors, hydrogen bond acceptors and/or other chemical features described in Tables 3-10. The combination of chemical features chosen for each search pharmacophore in a search set were chosen in an attempt to cover a diverse range of combinations of possible chemical interactions and to represent the protein ligand interactions that occur most frequently in the particular pharmacofamily.  
     [0182] Pharmacophore shape was derived using the program CATALYST, and was calculated using the Van der Waals surface for part or all of the structure of the averaged NAD(P) coordinates determined for a pharmacocluster. Desired hydrogen bonding features, water molecules and other chemical motifs were positioned in the pharmacophore model using the average coordinates determined for both the pharmacofamily and pharmacocluster.  
     [0183] The components of a pharmacophore model derived from the coordinates presented in Table 3 for pharmacofamily 1 are shown in FIG. 7. FIG. 7A shows the structure for the conformer model having coordinates listed in Table 3C with a superimposed volume defining the shape of the ligand and indicated by grey spheres. A hydrophobic feature was added to the pharmacophore model at the average position of the hydrophobic region of the nicotinamide ring as shown in FIG. 7B. Also shown in FIG. 7B is a hydrogen bond acceptor positioned at the average coordinates for the pyrophosphate using the averaged coordinates for the location of hydrogen bond acceptors utilized in all of the 17 polypeptides of the pharmacofamily. Finally, FIG. 7B shows a hydrogen bond donor positioned according to a position where a hydrogen bond donor of a ligand would be expected to have favorable interactions with hydrogen bond acceptors observed in 11 of the polypeptides of pharmacofamily 1. Thus, the hydrogen bond donor does not identify a position of an actual hydrogen bond donor in the NAD(P) ligand, but instead a location to where a potential ligand&#39;s hydrogen bond donor could make favorable interactions with the polypeptides of pharmacofamily 1. FIG. 7C shows the combined features of FIGS. 7A and 7B present in a pharmacophore model used to search a database of compounds.  
     [0184] To identify potential ligands that bind to polypeptides of pharmacofamily 1, computational searches were conducted using CATALYST. Searches were made by comparing the shape and combination of chemical features of the pharmacophore model, shown in FIG. 7, to the shape and features of molecules in the database.  
     [0185] An example of a compound identified using the pharmacophore model shown in FIG. 7C is TTE0008.025.D08. Using a binding assay similar to that described in Example V, compound TTE0008.025.D08 was shown to have inhibitory activity against pharmacofamily 1 member, dihydrodipicolinate reductase (IC 50 =2.8 μM)  
               TABLE 3A                          Pharmacofamily 1 Subset                                         RMSD                   from                   Family       Molecule #   pdb   type   Avg.                                     1   1A4I   Tetrahydrofolate Reductase (human)   0.75       2   1AXE   Alcohol Dehydrogenase (horse)   0.27       3   1DXY   D2-Hydroxyisocaproate Dehydrogenase   0.92               ( L. Casei )       4   1LDN   L-Lactate Dehydrogenase   0.41               ( B. Stearothermophilus )       5   1QR6   Malic Enzyme (human)   0.77       6   4MDH   Malate Dehydrogenase (pig)   0.65       7   1AGN   Alcohol Dehydrogenase   0.63               (human class IV sigma)       8   1B3R   Adenosylhomocysteine (rat)   0.93       9   1EMD   Malate Dehydrogenase   0.90               ( E. Coli )       10   1PJC   L-Alanine (Phormidium Lapideum)   0.79       11   1YKF   Alcohol Dehydrogenase   1.06               (Thermoanaerobium Brockii)       12   9LDB   Lactate Dehydrogenase (pig)   0.36       13   1ARZ   Dihydrodipicolinate Reductase ( E. Coli )   0.81       14   1BMD   Malate Dehydrogenase   0.68               ( Thermus Flavis )       15   1HYH   L2-Hydroxyisocaproate   0.57               Dehydrogenase               ( Lactobacillus Confusus )       16   1PSD   D3-Phosphoglycerate Dehydrogenase   0.78               ( E. Coli )       17   2NAD   Formate   0.91               Dehydrogenase               (methylotrophic               bacterium               pseudomonas sp               101)                  
 
     [0186]               TABLE 3B                          Polypeptide and Solvent Interactors (average coordinates)                                                 atom name   name   total   x   σx   y   σy   z   σz                                                         A15   ACC   15   −3.51   0.52   −1.48   0.44   −4.24   0.49       A22   ACC   17   3.14   0.41   −2.17   0.33   −4.13   1.01       A32   ACC   5   7.37   0.45   1.75   1.11   −8.24   0.79       A34   ACC   6   1.20   0.42   6.08   0.33   −1.83   1.39       A47   ACC   13   −12.03   0.32   −1.22   0.56   −3.63   0.52       A48   ACC   14   −10.58   0.37   −0.79   0.39   −4.81   0.25       A53   ACC   11   −2.66   0.31   −2.95   0.58   −1.04   0.46       A57   ACC   11   7.56   0.73   −2.50   0.42   −6.36   0.45       A96   ACC   6   10.24   0.42   0.50   0.64   −2.97   0.32       A99   ACC   4   1.44   0.22   6.19   0.26   −5.24   0.38       D9   DON   17   −7.70   0.67   2.30   0.43   −6.27   0.29       D1O   DON   17   −5.49   0.58   5.00   0.44   −5.79   0.28       D12   DON   17   −3.06   0.53   4.22   0.42   −7.05   0.38       D34   DON   2   7.05   0.16   1.64   0.42   −7.81   0.74       D36   DON   4   1.28   0.39   6.13   0.37   −1.01   0.70       D53   DON   5   −14.97   0.29   3.01   0.15   −1.95   0.55       D61   DON   11   2.46   0.64   −2.82   0.54   −0.35   0.58       D84   DON   11   4.78   0.45   0.00   0.90   −0.25   0.46       D105   DON   7   10.22   0.38   0.54   0.59   −3.10   0.45       D148   DON   4   −3.98   0.86   7.02   0.14   −1.61   0.33       W1   WAT   14   −4.88   0.34   1.26   0.38   −5.81   0.27       W6   WAT   6   −10.83   0.37   3.79   0.41   −3.11   0.70       W19   WAT   3   −12.43   0.10   2.22   0.31   −5.57   0.42                    
     [0187]               TABLE 3C                          NAD(P) Conformer Model                                             atom name   total   x   σx   y   σy   z   σz                                                     PA   17   −5.47   0.22   3.43   0.30   −1.84   0.27       O2A   17   −5.82   0.31   4.60   0.37   −2.38   0.65       O1A   17   −5.72   0.50   3.38   0.60   −0.59   0.64       O5′A   17   −6.13   0.25   2.22   0.25   −2.57   0.37       C5′A   17   −6.23   0.13   0.92   0.22   −2.20   0.23       C4′A   17   −7.50   0.39   0.21   0.43   −2.82   0.24       O4′A   17   −7.46   0.19   −1.07   0.14   −2.48   0.34       C3′A   17   −8.76   0.20   0.85   0.28   −2.35   0.43       O3′A   17   −9.62   0.37   1.13   0.33   −3.41   0.67       C2′A   17   −9.32   0.23   −0.09   0.31   −1.58   0.37       O2′A   17   −10.69   0.36   −0.06   0.51   −1.72   0.54       C1′A   17   −8.69   0.37   −1.29   0.45   −2.19   0.31       N9A   17   −8.88   0.18   −2.60   0.08   −1.36   0.24       C8A   17   −8.67   0.23   −2.75   0.20   −0.03   0.24       N7A   17   −8.84   0.32   −4.00   0.25   0.37   0.15       C5A   17   −9.17   0.33   −4.65   0.16   −0.75   0.14       C6A   17   −9.46   0.45   −6.00   0.16   −0.92   0.24       N6A   17   −9.49   0.52   −6.85   0.31   0.08   0.37       N1A   17   −9.74   0.48   −6.40   0.12   −2.17   0.29       C2A   17   −9.75   0.40   −5.55   0.19   −3.19   0.18       N3A   17   −9.49   0.29   −4.26   0.16   −3.07   0.11       C4A   17   −9.20   0.23   −3.82   0.08   −1.83   0.13       O3   17   −4.01   0.22   3.14   0.33   −2.03   0.34       PN   17   −2.81   0.17   3.31   0.22   −2.96   0.33       O1N   17   −2.32   0.49   4.39   0.63   −2.89   0.71       O2N   17   −3.16   0.47   3.27   0.61   −4.13   0.54       O5′N   17   −1.87   0.29   2.15   0.26   −2.49   0.48       C5′N   17   −1.92   0.27   0.87   0.27   −2.66   0.46       C4′N   17   −0.83   0.19   0.02   0.24   −2.14   0.36       O4′N   17   0.32   0.21   0.20   0.36   −2.95   0.27       C3′N   17   −0.36   0.23   0.40   0.28   −0.74   0.32       O3′N   17   −0.18   0.47   −0.71   0.40   0.01   0.35       C2′N   17   0.91   0.23   1.05   0.40   −0.94   0.21       O2′N   17   1.65   0.44   0.84   0.85   0.08   0.32       C1′N   17   1.45   0.18   0.41   0.23   −2.17   0.22       N1N   17   2.44   0.15   1.17   0.24   −2.89   0.19       C2N   17   3.61   0.20   0.61   0.24   −3.24   0.16       C3N   17   4.53   0.22   1.30   0.35   −3.97   0.23       C7N   17   5.81   0.29   0.71   0.58   −4.39   0.38       O7N   17   6.57   0.47   1.16   0.94   −4.83   0.51       N7N   17   6.03   0.44   −0.27   0.96   −4.27   0.71       C4N   17   4.30   0.34   2.55   0.41   −4.33   0.47       C5N   17   3.12   0.39   3.09   0.48   −3.96   0.64       C6N   17   2.19   0.27   2.41   0.44   −3.24   0.51       P2′   2   −11.69   0.02   1.32   0.36   −1.90   0.73       OP1   2   −12.69   0.51   0.79   0.45   −1.31   1.66       OP2   2   −12.01   0.86   1.94   0.08   −3.01   0.74       OP3   2   −11.04   0.61   2.17   0.59   −1.12   0.07                    
     [0188]               TABLE 3D                          Polypeptide and Solvent Interactors                                                         residue-                                       atom name   mol. #   residue #   total   x   σx   y   σy   z   σz                         Acceptors                                                     O   ALA1   215       −4.41       −1.37       −4.378           O   VAL2   268       −3.415       −1.508       −4.259       O   CYS4   95       −3.525       −1.391       −4.201       O   VAL5   392       −4.035       −1.223       −4.42       O   VAL6   86       −2.622       −2.525       −3.463       O   VAL7   268       −3.739       −1.583       −4.801       O   THR8   274       −3.374       −1.505       −3.621       O   SER9   76       −3.338       −0.96       −4.215       O   ALA10   237       −4.168       −1.334       −4.262       O   ALA11   242       −3.642       −1.13       −4.963       O   THR12   97       −2.827       −1.527       −3.709       O   PHE13   79       −3.279       −1.095       −4.527       O   VAL14   86       −2.698       −2.451       −3.496       O   THR15   96       −3.708       −1.231       −4.403       O   ASN17   254       −3.847       −1.386       −4.942       A15   ACC   15   15   −3.508   0.51867   −1.481   0.444684   −4.244   0.48666       O   CYS1   236       3.015       −2.169       −3.644       O   VAL2   292       3.319       −2.239       −3.966       O   THR3   232       3.626       −2.073       −5.277       O   ALA4   136       2.873       −1.964       −3.884       O   LEU5   419       3.566       −2.603       −2.54       O   VAL6   128       2.902       −2.638       −3.394       O   VAL7   292       3.435       −2.183       −4.536       O   ILE8   298       2.705       −2.013       −5.149       O   ILE9   117       3.267       −2.016       −3.572       O   VAL10   266       3.531       −1.908       −3.445       O   VAL11   265       2.245       −2.153       −5.774       O   VAL12   138       3.423       −2.49       −3.658       O   GLY13   102       3.045       −2.197       −3.332       O   VAL14   128       2.473       −2.343       −3.403       O   ILE15   141       3.095       −2.691       −3.316       O   ALA16   238       3.132       −1.372       −5.812       O   THR17   282       3.668       −1.893       −5.571       A22   ACC   22   17   3.1365   0.40729   −2.173   0.325811   −4.134   1.01093       OG1   THR1   279       6.933       1.937       −8.332       O   ALA3   297       7.27       2.615       −9.402       OD1   ASN8   345       7.341       0.057       −7.801       SG   CYS11   295       8.12       2.802       −8.368       OG   SER17   334       7.164       1.343       −7.29       A32   ACC   32   5   7.3656   0.44907   1.7508   1.109256   −8.239   0.78586       SG   CYS2   46       1.759       6.095       −1.597       OG   SER6   240       1.154       5.714       −0.415       SG   CYS7   46       1.39       6.091       −1.637       OD1   ASN 8   190       1.47       6.205       −3.174       OG   SER9   222       0.831       6.625       −0.409       OG   SER10   133       0.616       5.761       −3.752       A34   ACC   34   6   1.2033   0.42444   6.0818   0.331268   −1.831   1.38661       OD1   ASP2   223       −12.06       −1.364       −3.72       OD1   ASP3   175       −12.31       −1.116       −2.892       OD1   ASP4   52       −12.29       −1.122       −4.018       OD2   ASP6   41       −12.14       −1.461       −3.317       OD2   ASP7   223       −12.26       0.192       −5.072       OE1   GLU8   242       −12.17       −0.604       −3.687       OD1   ASP9   34       −11.26       −2.188       −3.753       OD2   ASP10   197       −12.39       −1.306       −3.358       OD1   ASP12   53       −11.79       −1.526       −3.647       OE1   GLU14   41       −11.76       −1.641       −3.303       OD1   ASP15   53       −11.95       −1.38       −3.606       OD1   ASP16   181       −12.33       −1.128       −3.23       OD1   ASP17   221       −11.74       −1.235       −3.585       A47   ACC   47   13   −12.03   0.32497   −1.221   0.556926   −3.63   0.51984       OD2   ASP2   223       −10.46       −0.712       −5.067       OD2   ASP3   175       −10.78       −0.582       −4.327       OD2   ASP4   52       −10.23       −0.845       −4.641       OD1   ASP6   41       −10.8       −0.87       −4.98       OD1   ASP7   223       −10.78       −1.36       −4.58       OE2   GLU8   242       −10.46       0.103       −4.803       OD2   ASP9   34       −9.97       −1.147       −5.144       OD1   ASP10   197       −10.71       −0.756       −4.609       OD2   ASP12   53       −10.1       −0.987       −4.85       OE1   GLU13   38       −11.44       −1.444       −4.68       OE2   GLU14   41       −10.7       −0.348       −4.708       OD2   ASP15   53       −10.49       −0.813       −5.102       OD2   ASP16   181       −10.87       −0.595       −4.761       OD2   ASP17   221       −10.38       −0.678       −5.134       A48   ACC   48   14   −10.58   0.37106   −0.788   0.394449   −4.813   0.24544       O   ILE2   269       −2.445       −2.256       −0.193       O   VAL3   205       −2.446       −3.051       −1.43       O   ALA4   96       −3.129       −3.442       −1.462       OG   SER6   88       −2.227       −3.432       −0.657       O   ILE7   269       −2.544       −2.277       −0.546       O   ALA9   77       −2.936       −3.387       −1.405       O   VAL10   238       −2.653       −2.624       −0.587       O   ALA12   98       −3.101       −4.038       −1.238       O   THR13   80       −2.808       −2.299       −1.065       O   LEU15   97       −2.726       −2.902       −1.459       O   VAL16   211       −2.296       −2.734       −1.354       A53   ACC   53   11   −2.665   0.30695   −2.949   0.580767   −1.036   0.45723       O   ALA2   317       7.471       −2.554       −6.143       OD2   ASP3   258       8.172       −2.402       −6.366       OG   SER4   161       7.049       −2.744       −6.487       O   LEU6   154       8.715       −2.807       −5.528       O   CYS7   317       7.229       −2.526       −6.12       O   VAL9   146       7.764       −1.709       −6.821       OG   SER12   163       6.66       −2.956       −6.767       O   MET14   154       8.194       −2.694       −5.797       OG1   THR15   166       6.339       −2.915       −6.856       OD2   ASP16   264       8.236       −1.758       −6.216       OD1   ASP17   308       7.288       −2.414       −6.878       A57   ACC   57   11   7.5561   0.73228   −2.498   0.420521   −6.362   0.45202       ND1   HIS4   193       10.626       0.61       −3.116       ND1   HIS6   186       10.014       −0.093       −2.576       ND1   HIS9   177       10.504       1.695       −3.436       ND1   HIS12   195       10.555       0.375       −3.145       ND1   HIS14   186       9.53       0.058       −2.803       ND1   HIS15   198       10.182       0.378       −2.754       A96   ACC   96   6   10.235   0.41864   0.5038   0.635226   −2.972   0.31587       O   THR4   247       1.697       6.212       −4.932       O   SER6   241       1.512       5.836       −4.992       O   THR12   246       1.401       6.459       −5.282       O   THR15   248       1.165       6.252       −5.758       A99   ACC   99   4   1.4438   0.22235   6.1898   0.25949   −5.241   0.37703                 Donors                                                     N   SER1   174       −6.971       2.982       −6.833           N   GLY2   201       −7.051       2.265       −6.475       N   GLY3   154       −8.12       2.219       −6.064       N   GLY4   29       −7.293       1.675       −6.476       N   GLY5   313       −7.132       2.483       −6.314       N   GLY6   13       −8.808       2.734       −6.39       N   GLY7   201       −7.089       2.378       −6.44       N   GLY8   221       −7.171       2.192       −6.095       N   GLY9   10       −8.673       2.272       −6.033       N   GLY10   176       −7.708       1.61       −6.214       N   GLY11   176       −7.166       2.546       −5.844       N   GLY12   30       −7.358       1.997       −6.529       N   GLY13   15       −8.347       3.129       −5.659       N   GLY14   13       −8.993       2.681       −6.03       N   GLY15   30       −7.35       1.898       −6.417       N   GLY16   160       −7.754       2.152       −6.234       N   GLY17   200       −7.84       1.819       −6.562       D9   DON   9   17   −7.696   0.66531   2.296   0.431519   −6.271   0.29226       OG   SER1   174       −4.169       3.811       −6       N   GLY2   202       −5.086       5.296       −6.262       N   HIS3   155       −6.067       5.154       −5.788       N   PHE4   30       −5.313       4.474       −6.084       N   GLU5   314       −5.224       5.566       −5.679       N   GLN6   14       −6.138       5.075       −5.705       N   GLY7   202       −5.115       5.35       −5.842       N   ASP8   222       −4.822       4.792       −5.908       N   GLY9   11       −6.29       5.058       −5.51       N   VAL10   177       −5.677       4.573       −6.103       N   PRO11   177       −5.131       5.547       −5.772       N   ALA12   31       −5.256       4.982       −5.907       N   ARG13   16       −5.501       5.429       −5.154       N   GLN14   14       −6.311       5.136       −5.537       N   ASN15   31       −5.383       4.826       −5.877       N   HIS16   161       −5.882       5.126       −5.388       N   ARG17   201       −6       4.758       −5.866       D10   DON   10   17   −5.492   0.57597   4.9972   0.439163   −5.787   0.2765       N   VAL1   177       −2.231       4.172       −8.191       N   VAL2   203       −2.521       4.333       −7.106       N   ILE3   156       −3.616       4.356       −7.328       N   VAL4   31       −2.539       3.702       −7.072       N   ALA5   315       −2.542       4.593       −6.385       N   ILE6   15       −3.471       4.432       −7.048       N   VAL7   203       −2.643       4.75       −6.934       N   VAL8   223       −2.523       3.344       −6.862       N   ILE9   12       −3.863       4.694       −6.846       N   VAL10   178       −3.08       3.512       −7.145       N   VAL11   178       −2.953       4.368       −7.142       N   VAL12   32       −2.793       3.892       −6.902       N   MET13   17       −3.251       4.443       −6.48       N   ILE14   15       −3.826       4.526       −7.009       N   VAL15   32       −2.951       3.934       −7.082       N   ILE16   162       −3.722       4.618       −7.096       N   ILE17   202       −3.556       4.064       −7.229       D12   DON   12   17   −3.064   0.53062   4.2196   0.418148   −7.05   0.38051       OG1   THR1   279       6.933       1.937       −8.332       OG   SER17   334       7.164       1.343       −7.29       D34   DON   34   2   7.0485   0.16334   1.64   0.420021   −7.811   0.73681       SG   CYS2   46       1.759       6.095       −1.597       OG   SER6   240       1.154       5.714       −0.415       SG   CYS7   46       1.39       6.091       −1.637       OG   SER9   222       0.831       6.625       −0.409       D36   DON   36   4   1.2835   0.39114   6.1313   0.374531   −1.015   0.6959       ND2   ASN2   225       −14.56       3.056       −1.923       ND2   ASN7   225       −15.12       3.202       −1.587       ND2   ASN10   199       −14.92       2.944       −1.285       N   ARG11   200       −15.34       3.078       −2.669       ND2   ASN15   55       −14.92       2.794       −2.271       D53   DON   53   5   −14.97   0.2886   3.0148   0.153705   −1.947   0.54651       N   VAL2   294       2.334       −2.69       −0.397       N   ASN4   138       2.277       −2.379       0.029       N   ASN5   421       2.644       −2.578       0.583       N   ASN6   130       2.063       −2.785       −0.349       N   VAL7   294       2.742       −3.152       −1.066       N   ASN9   119       2.504       −2.09       −0.346       N   VAL10   268       4.124       −4.101       −1.602       N   ASN12   140       2.522       −2.522       −0.359       N   THR13   104       2.237       −3.331       0.05       N   ASN14   130       1.53       −2.648       −0.196       N   ASN15   143       2.106       −2.7       −0.15       D61   DON   61   11   2.4621   0.64303   −2.816   0.543046   −0.346   0.5762       NH1   ARG3   234       4.587       −0.618       0.683       ND2   ASN4   138       5.58       −1.025       −0.579       ND2   ASN5   421       4.967       −0.91       −0.857       ND2   ASN6   130       4.796       0.498       −0.376       ND2   ASN9   119       4.776       1.072       −0.333       ND2   ASN12   140       4.874       0.88       −0.41       ND2   ASN14   130       3.87       0.241       −0.144       ND2   ASN15   143       4.582       0.661       −0.159       NH1   ARG16   240       5.381       −0.809       −0.472       NH2   ARG16   240       4.57       1.118       0.462       NH1   ARG17   284       4.55       −1.163       −0.589       D84   DON   84   11   4.7757   0.4524   −0.005   0.904651   −0.252   0.45674       ND1   HIS4   193       10.626       0.61       −3.116       ND1   HIS6   186       10.014       −0.093       −2.576       ND1   HIS9   177       10.504       1.695       −3.436       N   ASN10   299       10.126       0.746       −3.889       ND1   HIS12   195       10.555       0.375       −3.145       ND1   HIS14   186       9.53       0.058       −2.803       ND1   HIS15   198       10.182       0.378       −2.754       D105   DON   105   7   10.22   0.38439   0.5384   0.587058   −3.103   0.45095       NE   ARG9   80       −3.463       6.961       −1.445       NH1   ARG12   101       −3.963       7.113       −1.977       NE   ARG13   16       −3.284       7.146       −1.239       NE2   GLN14   14       −5.2       6.85       −1.788       D148   DON   148   4   −3.978   0.86417   7.0175   0.137697   −1.612   0.33227                 Waters                                                     O   HOH1   37       −4.852       0.916       −5.955           O   HOH2   6       −4.639       1.155       −5.586       O   HOH3   341       −5.542       1.121       −5.837       O   HOH4   4       −4.423       0.776       −5.661       O   HOH5   8       −4.893       1.328       −5.536       O   HOH6   58       −4.815       1.672       −6.392       O   HOH9   316       −5.086       1.405       −5.627       O   HOH10   3       −4.816       0.793       −5.596       O   HOH12   21       −4.532       0.966       −5.406       O   HOH13   810       −4.598       2.049       −5.765       O   HOH14   20       −5.549       1.612       −6.137       O   HOH15   370       −4.601       1.061       −5.784       O   HOH16   566       −4.928       1.656       −6.021       O   HOH17   35       −5.091       1.06       −5.977       W1   WAT   1   14   −4.883   0.34302   1.255   0.378799   −5.806   0.26779       O   HOH1   238       −11.09       4.575       −3.702       O   HOH4   62       −10.9       3.609       −3.539       O   HOH6   71       −10.22       3.569       −2.078       O   HOH10   92       −11.17       3.592       −2.43       O   HOH15   395       −10.54       3.897       −3.702       O   HOH17   199       −11.04       3.484       −3.197       W6   WAT   6   6   −10.83   0.37024   3.7877   0.410386   −3.108   0.69569       O   HOH3   360       −12.48       2.562       −5.14       O   HOH5   495       −12.31       1.96       −5.591       O   HOH17   439       −12.49       2.145       −5.979       W19   WAT   19   3   −12.43   0.09854   2.2223   0.308361   −5.57   0.41989                    
     [0189]               TABLE 4A                          Pharmacofamily 2 Subset                                         rmsd                   from                   Family       molecule #   pdb   type   Avg.               1   1CH6   Glutamine Dehydrogenase (cow)   0.58       2   1CER   Glyceraldehyde-3-phosphate D.   0.31               ( Thermus aquaticus )       3   1GYP   Glyceraldehyde-3-phosphate D.   0.34               ( Leishmania Mexicana )       4   2HDH   L3-hydroxyacyl CoA D. (human)   0.33       5   1BXG   Phenylalanine D. (Rhodococcus sp.)   0.59                    
     [0190]               TABLE 4B                          Polypeptide and Solvent Interactors (average coordinates)                                                 atom   residue-                                   name   mol. #   total   x   σx   y   σy   z   σz                         Acceptors                                                 A4   ACC   1   1.10   —   −4.12   —   7.02   —       A21   ACC   5   −7.31   0.94   7.30   0.23   1.70   0.42       A24(D28)   ACC   2   −9.52   0.99   4.80   0.06   −0.72   0.16       A26   ACC   3   −0.46   0.40   0.62   0.26   1.22   0.20       A31   ACC   5   5.50   0.30   1.15   0.72   4.41   0.31       A36   ACC   4   8.61   0.66   −1.12   0.22   6.56   0.54       A45   ACC   2   −5.73   0.51   5.08   0.20   −7.62   0.21       A47   ACC   2   −2.38   0.16   1.11   0.32   1.01   0.14       A57   ACC   3   4.82   0.39   1.19   0.27   12.29   0.39       A74   ACC   1   1.86   —   −2.87   —   1.92   —       A75   ACC   1   3.26   —   −4.52   —   2.27   —       A80   ACC   1   5.45   —   −2.88   —   6.60   —                 Donors                                                 D21   DON   5   −3.69   0.38   6.81   0.18   5.90   0.25       D22   DON   6   −2.46   0.68   4.98   0.17   8.91   0.34       D24   DON   3   0.28   0.18   4.88   0.18   8.67   0.22       D27   DON   5   −8.64   0.42   7.78   0.77   −0.88   0.39       D28(A24)   DON   3   −9.48   0.70   4.58   0.39   −0.74   0.11       D37   DON   2   4.89   0.32   −0.97   0.08   1.99   0.02       D38   DON   2   5.09   0.86   −3.25   0.34   4.18   0.69       D84   DON   1   −10.79   —   7.18   —   0.38   —                 Water                                                 W1   WAT   2   −1.68   0.35   5.44   0.29   5.49   0.17                    
     [0191]               TABLE 4C                          NAD(P) Conformer Model                                             atom name   total   x   σx   y   σy   z   σz                                                     PA   5   −4.24   0.19   1.80   0.11   6.48   0.23       O1A   5   −5.08   0.52   0.75   0.25   6.07   0.45       O2A   5   −4.62   0.23   2.55   0.14   7.71   0.23       O5′A   5   −3.99   0.30   2.86   0.25   5.34   0.17       C5′A   5   −4.32   0.41   2.73   0.18   4.00   0.21       C4′A   5   −4.89   0.25   4.02   0.13   3.50   0.21       O4′A   5   −4.66   0.06   4.05   0.14   2.08   0.25       C3′A   5   −6.39   0.28   4.19   0.08   3.68   0.05       O3′A   5   −6.70   0.35   5.46   0.12   4.28   0.08       C2′A   5   −6.97   0.10   3.99   0.10   2.31   0.09       O2′A   5   −8.13   0.10   4.75   0.15   2.08   0.23       C1′A   5   −5.83   0.08   4.47   0.05   1.44   0.09       N9A   5   −5.83   0.28   3.93   0.08   0.08   0.09       C8A   5   −6.06   0.43   2.68   0.11   −0.38   0.12       N7A   5   −5.93   0.46   2.59   0.16   −1.71   0.12       C5A   5   −5.61   0.32   3.84   0.14   −2.10   0.08       C6A   5   −5.33   0.30   4.34   0.13   −3.42   0.12       N6A   5   −5.40   0.43   3.59   0.10   −4.50   0.12       N1A   5   −5.02   0.16   5.67   0.11   −3.48   0.08       C2A   5   −4.98   0.15   6.46   0.10   −2.39   0.12       N3A   5   −5.23   0.19   6.03   0.05   −1.15   0.07       C4A   5   −5.53   0.23   4.70   0.09   −1.02   0.07       O3   5   −2.84   0.26   1.29   0.52   6.62   0.32       PN   5   −1.40   0.20   1.34   0.15   7.08   0.12       O1N   5   −1.38   0.09   0.38   0.31   7.92   0.81       O2N   5   −1.08   0.38   2.54   0.62   7.45   0.53       O5′N   5   −0.51   0.24   1.01   0.62   5.97   0.12       C5′N   5   −0.17   0.26   1.53   0.19   4.90   0.36       C4′N   5   1.07   0.22   0.97   0.17   4.29   0.20       O4′N   5   2.15   0.28   1.09   0.07   5.24   0.14       C3′N   5   1.04   0.26   −0.49   0.20   3.88   0.12       O3′N   5   1.75   0.42   −0.71   0.28   2.70   0.12       C2′N   5   1.72   0.26   −1.20   0.10   5.03   0.16       O2′N   5   2.24   0.33   −2.42   0.17   4.63   0.40       C1′N   5   2.76   0.26   −0.18   0.11   5.44   0.12       NN1   2   3.11   0.26   −0.28   0.02   6.85   0.14       C2N   5   2.34   0.16   −0.31   0.27   7.90   0.13       C3N   5   2.82   0.09   −0.46   0.18   9.20   0.15       C7N   5   1.92   0.16   −0.56   0.40   10.40   0.11       O7N   5   2.01   0.59   −0.69   0.67   11.28   0.54       NN7   2   0.66   0.05   −0.71   1.04   10.09   0.19       C4N   5   4.19   0.10   −0.48   0.22   9.46   0.21       C5N   5   5.02   0.08   −0.40   0.46   8.34   0.31       C6N   5   4.56   0.17   −0.26   0.34   7.06   0.27                    
     [0192]               TABLE 4D                          Polypeptide and Solvent Interactors                                                         residue-                                       atom name   mol. #   residue #   total   x   σx   y   σy   z   σz                         Acceptors                                                     OD1   ASN 1   168       1.095       −4.122       7.015           A4   ACC   4   1   1.095       −4.122       7.015       O   PHE 1   252       −5.191       8.539       6.797       O   PHE 2   8       −5.255       8.065       6.21       O   PHE 3   10       −4.805       8.465       5.853       O   GLY 4   23       −4.854       8.511       7.292       O   LEU 5   183       −5.255       8.273       6.6       A14   ACC   14   5   −5.072   0.22358   8.3706   0.199937   6.5504   0.55124       OE1   GLU 1   275       −6.7       7.256       2.045       OD1   ASP 2   32       −8.197       7.417       1.98       OD1   ASP 3   38       −5.963       7.483       1.973       OD1   ASP 4   45       −7.792       7.445       1.259       OD1   ASP 5   205       −7.896       6.916       1.22       A21   ACC   21   5   −7.31   0.94194   7.3034   0.233204   1.6954   0.41735       OG   SER 1   276       −10.22       4.761       −0.611       OG1   THR 5   206       −8.824       4.845       −0.836       A24   ACC   24   2   −9.523   0.98783   4.803   0.059397   −0.724   0.1591       O   ALA 1   326       −0.312       0.409       1.158       O   ILE 4   108       −0.908       0.539       1.439       O   ALA 5   239       −0.153       0.904       1.064       A26   ACC   26   3   −0.458   0.39802   0.6173   0.256629   1.2203   0.19512       O   GLY 1   347       5.243       2.256       4.521       O   THR 2   119       5.496       1.074       4.297       O   SER 3   134       5.492       0.484       4.132       O   ASN 4   135       5.99       0.551       4.206       O   ALA 5   260       5.254       1.362       4.897       A31   ACC   31   5   5.495   0.30275   1.1454   0.720452   4.4106   0.30869       OD1   ASN 1   374       9.186       −0.987       5.966       NE2   HIS 4   158       7.894       −1.364       7.028       OD1   ASN 5   288       8.756       −0.995       6.691       A36   ACC   36   4   8.612   0.65793   −1.115   0.215389   6.5617   0.54268       O   LYS 2   77       −6.092       4.938       −7.77       O   GLN 3   91       −5.369       5.217       −7.467       A45   ACC   45   2   −5.731   0.51124   5.0775   0.197283   −7.619   0.21425       O   THR 2   96       −2.488       1.334       0.905       O   THR 3   111       −2.265       0.887       1.109       A47   ACC   47   2   −2.377   0.15768   1.1105   0.316077   1.007   0.14425       O   GLY 2   97       −0.425       −2.183       −0.802       O   GLY 3   112       −0.663       −2.629       −0.591       O   VAL 4   109       −1.565       −1.362       −0.563       A49   ACC   49   3   −0.884   0.60137   −2.058   0.642683   −0.652   0.13066       O   ASN 2   313       4.587       0.929       12.609       O   ASN 3   335       5.271       1.175       12.408       OG1   THR 5   153       4.596       1.474       11.859       A57   ACC   57   3   4.818   0.39234   1.1927   0.272929   12.292   0.38822       OE1   GLU 4   110       1.86       −2.87       1.915       A74   ACC   74   1   1.86       −2.87       1.915       OE2   GLU 4   110       3.257       −4.521       2.267       A75   ACC   75   1   3.257       −4.521       2.267       OG   SER 4   137       5.445       −2.882       6.6       A80   ACC   80   1   5.445       −2.882       6.6                 Donors                                                     N   PHE 1   252       −3.795       8.382                   N   PHE 2   8       −3.513       8.186       3.399       N   PHE 3   10       −3.274       8.183       2.802       N   GLY 4   23       −3.891       8.194       3.841       N   LEU 5   183       −3.951       8.196       3.424       D20   DON   20   5   −3.685   0.28452   8.2282   0.086146   3.4252   0.39277       N   GLY 1   253       −3.608       7.062       6.079       N   GLY 2   9       −3.411       6.805       5.974       N   GLY 3   11       −3.279       6.847       5.562       N   GLY 4   24       −3.951       6.79       6.145       N   GLY 5   184       −4.182       6.562       5.718       D21   DON   21   5   −3.686   0.37537   6.8132   0.17801   5.8956   0.24739       N   ASN 1   254       −2.527       5.077       8.825       N   ARG 2   10       −2.87       4.723       8.75       N   ARG 3   12       −2.609       4.907       8.456       N   LEU 4   25       −3       5.05       9.249       N   VAL 5   186       −1.3       5.165       9.257       D22   DON   22   6   −2.461   0.67675   4.9844   0.173072   8.9074   0.34432       N   VAL 1   255       0.427       5.067       8.691       N   ILE 2   11       0.083       4.702       8.883       N   ILE 3   13       0.32       4.862       8.448       D24   DON   24   3   0.2767   0.17605   4.877   0.182962   8.674   0.218       N   SER 1   276       −8.021       6.758       −1.068       N   LEU 2   33       −8.808       8.195       −0.527       N   MET 3   39       −9.137       8.038       −0.417       N   GLN 4   46       −8.461       8.672       −1.048       N   THR 5   206       −8.757       7.228       −1.324       D27   DON   27   5   −8.637   0.41955   7.7782   0.77195   −0.877   0.38718       OG   SER 1   276       −10.22       4.761       −0.611       NE2   GLN 4   46       −9.404       4.137       −0.763       OG1   THR 5   206       −8.824       4.845       −0.836       D28   DON   28   3   −9.483   0.70184   4.581   0.386802   −0.737   0.11479       N   ASN 1   349       4.665       −0.919       1.972       N   ASN 5   262       5.113       −1.03       1.998       D37   DON   37   2   4.889   0.31678   −0.975   0.078489   1.985   0.01838       ND2   ASN 1   349       4.485       −3.489       4.665       N   SER 4   137       5.697       −3.011       3.686       D38   DON   38   2   5.091   0.85701   −3.25   0.337997   4.1755   0.69226       N   ASP 5   207       −10.79       7.181       0.384       D84   DON   84   1   −10.79       7.181       0.384                 Waters                                                     O   HOH 4   888       −1.436       5.238       5.606           O   HOH 5   888       −1.931       5.647       5.365       W1   WAT   1   1   −1.684   0.35002   5.4425   0.289207   5.4855   0.17041                    
     [0193]               TABLE 5A                          Pharmacofamily 3 Subset                                         RMSD                   from                   Family       Molecule #   pdb   type   Avg.                                     1   1A27   17b-Hydroxysteroid Dehydrogenase   0.35               (human)       2   1AE1   Tropinone Reductase   0.33       3   1AHH   7a-Hydroxysteroid Dehydrogenase   0.51       4   1BDB   Cis-Biphenyl-2,3-Dihydrodiol-2,3-   0.28               Dehydrogenase       5   1BSV   GDP-Fucose Synthase   0.87       6   1CYD   Carbonyl Reductase   0.26       7   1ENZ   Enoyl Acyl Carrier Protein Reductase   0.66       8   1NAI   UDP-Galactose Epimerase   0.45       9   1SEP   Sepiapterin Reductase   0.43       10   1YBV   Trihydroxynaphthalene Reductase   0.70       11   1HSD   2a-20b-Hydroxysteroid Dehydrogenase   0.55       12   1DIR   Dihydropteridine Reductase   0.75                    
     [0194]               TABLE 5B                          Polypeptide and Solvent Interactors (average coordinates)                                                 atom name   Name   total   x   σx   y   σy   z   σz                         Acceptors                                                 A5(D5)   ACC   4   −9.243   0.6136   −6.385   0.485759   7.5835   0.60521       A20   ACC   10   −2.055   0.62558   −12.31   0.344913   15.347   0.71676       A24   ACC   12   −0.64   0.89267   −1.809   0.373379   8.7658   0.6637       A32   ACC   12   2.8272   0.30273   5.1573   0.670541   10.018   0.502       A34(D34)   ACC   9   1.8439   0.50418   7.7642   0.274322   13.139   0.30794       A36(D38)   ACC   12   −0.113   0.24453   4.7021   0.586493   13.952   0.24008       A38   ACC   11   1.2485   0.72569   9.7629   0.441462   9.482   0.48385       A40   ACC   10   −2.496   0.41035   10.064   0.558296   8.9034   0.77733       A42   ACC   9   −7.86   0.22197   8.1173   0.560664   9.1394   0.53745       A44(D47)   ACC   8   −8.336   0.72492   4.1414   0.508189   9.0466   0.81437       A68   ACC   5   −6.27   0.3454   −7.233   0.556879   7.5474   0.30836                 Donors                                                 D5(A5)   DON   6   −9.892   1.12248   −6.493   0.603878   7.9562   0.75319       D7   DON   2   −9.66   0.00919   −1.843   0.165463   8.0065   0.15061       D9   DON   12   −6.057   0.41875   1.6692   0.293883   4.914   0.25367       D21   DON   10   0.0467   0.43511   −11.62   0.342553   11.981   0.91633       D34(A34)   DON   9   1.8439   0.50418   7.7642   0.274322   13.139   0.30794       D38(A36)   DON   11   −0.113   0.24453   4.7021   0.586493   13.952   0.24008       D40   DON   12   2.4988   0.36354   1.5627   0.445563   12.367   0.3007       D45   DON   10   −5.476   0.54512   9.6232   0.478163   8.6938   0.41629       D47(A44)   DON   6   −7.675   0.22275   3.8897   0.368935   9.5875   1.11949                 Water                                                 W4   WAT   9   −4.738   0.3561   −1.037   0.298174   6.477   0.47268       W5   WAT   4   2.6995   0.66749   −0.925   0.394841   9.7795   0.39679       W9   WAT   9   3.273   0.73202   −1.012   0.573841   12.802   0.86657       W11   WAT   6   −6.007   0.19132   −1.829   0.200188   13.702   0.2296                    
     [0195]               TABLE 5C                          NAD(P) Conformer Model                                             atom                                   name   total   x   σx   y   σy   z   σz                                                     PA   12   −6.94   0.27682   −0.359   0.12062   10.196   0.3132       O1A   12   −7.187   0.50362   −0.724   0.311997   11.568   0.35149       O2A   12   −8.039   0.23033   0.0836   0.236246   9.4105   0.49965       O5′A   12   −6.324   0.33618   −1.599   0.152174   9.5178   0.48615       C5′A   12   −5.31   0.27378   −2.37   0.252109   9.8483   0.42032       C4′A   12   −5.39   0.23487   −3.716   0.196458   9.4463   0.27041       O4′A   12   −4.443   0.17889   −4.486   0.362347   10.152   0.45942       C3′A   12   −6.677   0.26263   −4.369   0.172555   9.6349   0.38881       O3′A   12   −7.077   0.60241   −4.969   0.317672   8.502   0.51095       C2′A   12   −6.427   0.2192   −5.392   0.18758   10.719   0.34471       O2′A   12   −7.207   0.43164   −6.53   0.229629   10.538   0.52325       C1′A   12   −4.996   0.2692   −5.707   0.273621   10.514   0.28506       N9A   12   −4.338   0.16157   −6.335   0.231445   11.625   0.21234       C8A   12   −4.321   0.18366   −5.957   0.287413   12.906   0.25525       N7A   12   −3.708   0.19062   −6.853   0.38173   13.663   0.14123       C5A   12   −3.345   0.167   −7.802   0.336217   12.81   0.08303       C6A   12   −2.685   0.29854   −8.972   0.409416   13.085   0.20366       N6A   12   −2.353   0.40839   −9.302   0.557888   14.313   0.25603       N1A   12   −2.439   0.38208   −9.778   0.395034   12.051   0.30817       C2A   12   −2.826   0.38939   −9.443   0.393263   10.824   0.25264       N3A   12   −3.468   0.30202   −8.33   0.362823   10.533   0.10763       C4A   12   −3.726   0.15519   −7.514   0.288774   11.545   0.09427       O3   12   −5.803   0.3398   0.7197   0.195007   10.133   0.2437       PN   12   −5.139   0.15801   1.6654   0.119922   9.0683   0.30355       O1N   12   −5.513   0.30736   2.837   0.583522   9.2767   0.62893       O2N   12   −5.465   0.24079   1.3618   0.579089   7.8578   0.57479       O5′N   12   −3.623   0.17622   1.5297   0.454033   9.3583   0.46312       C5′N   12   −2.693   0.23195   0.8583   0.262204   8.7345   0.42939       C4′N   12   −1.318   0.21148   1.311   0.296942   9.1289   0.3066       O4′N   12   −1.218   0.20704   2.7193   0.281646   8.9326   0.16566       C3′N   12   −1.013   0.32386   1.0723   0.442515   10.567   0.32728       O3′N   12   0.2498   0.44917   0.5617   0.307845   10.743   0.48253       C2′N   12   −1.071   0.433   2.4089   0.415664   11.195   0.2308       O2′N   12   −0.264   0.66117   2.4258   0.295043   12.27   0.42485       C1′N   12   −0.686   0.16367   3.3148   0.345237   10.094   0.21704       N1N   12   −1.199   0.0741   4.663   0.296089   10.265   0.17649       C2N   12   −2.555   0.09392   4.903   0.192059   10.257   0.12994       C3N   12   −3.045   0.15342   6.1843   0.177656   10.413   0.22204       C7N   12   −4.492   0.16456   6.5182   0.22133   10.516   0.29939       O7N   12   −4.912   0.2416   7.4728   0.677128   10.793   0.41339       N7N   12   −5.319   0.24693   5.7468   0.705835   10.295   0.42085       C4N   12   −2.139   0.24246   7.2165   0.188473   10.586   0.22472       C5N   12   −0.79   0.23943   6.9686   0.319535   10.576   0.31698       C6N   12   −0.303   0.12398   5.6903   0.375214   10.42   0.30569       P2′   6   −8.185   0.35266   −7.167   0.53148   11.087   0.59086       OP1   6   −8.864   0.54615   −7.461   1.469844   10.462   0.97819       OP2   6   −8.7   0.98419   −7.192   1.218849   11.053   0.61709       OP3   6   −7.909   0.42562   −7.322   0.715581   12.334   0.66989                    
     [0196]               TABLE 5D                          Polypeptide and Solvent Interactors                                                     atom   residue-                                       name   mol. #   residue #   total   x   σx   y   σy   z   σz                         Acceptors                                                     O   GLY 1   9       −4.643       −4.27       6.043           O   GLY 2   28       −4.558       −4.117       5.821       O   GLY 3   18       −4.048       −4.273       6.088       O   GLY 4   12       −4.135       −3.933       6.033       O   GLY 5   10       −4.432       −4.169       5.555       O   GLY 6   14       −4.284       −4.355       6.044       O   GLY 7   14       −6.249       −5.065       6.52       O   GLY 8   7       −4.849       −3.848       5.762       O   GLY 9   15       −4.591       −3.878       5.357       O   GLY 10   36       −4.346       −4.384       5.754       O   GLY 11   13       −5.058       −4.026       6.159       O   GLY 12   13       −5.622       −4.826       5.87       A1   ACC   1   12   −4.735   0.64211   −4.262   0.369162   5.9172   0.30204       OG   SER 1   11       −9.556       −5.885       8.172       OG   SER 2   30       −9.127       −6.766       7.066       OG   SER 8   36       −9.85       −6.053       8.039       OG   SER 9   17       −8.437       −6.835       7.057       A5   ACC   5   4   −9.243   0.6136   −6.385   0.485759   7.5835   0.60521       OD1   ASP 1   65       −1.811       −12.31       14.284       OD1   ASP 2   78       −2.629       −12.15       15.593       OD2   ASP 3   68       −1.583       −12.75       16.533       OD2   ASP 4   59       −2.534       −12.5       15.835       OD1   ASP 6   60       −2.109       −11.85       15.924       OD1   ASP 7   64       −2.151       −12.8       14.21       OD2   ASP 8   58       −2.841       −11.82       15.085       OD1   ASP 9   70       −2.628       −12.13       15.425       OD1   ASN 10   87       −1.218       −12.17       15.492       OD1   ASP 11   60       −1.044       −12.57       15.088       A20   ACC   20   10   −2.055   0.62558   −12.31   0.344913   15.347   0.71676       O   ASN 1   90       −0.231       −1.804       8.763       O   ASN 2   106       −0.349       −1.37       8.814       O   ASN 3   95       0.522       −1.353       8.638       O   ASN 4   86       0.101       −1.425       8.863       O   ALA 5   62       −1.699       −2.266       8.014       O   ASN 6   83       −0.206       −1.697       9.086       O   ALA 7   94       −2.052       −2.486       7.753       O   PHE 8   80       −1.247       −1.892       9.217       O   ASN 9   101       −0.131       −1.62       8.833       O   ASN 10   114       0.159       −1.576       9.032       O   ASN 11   87       −0.643       −1.744       9.231       O   VAL 12   82       −2.283       −1.889       7.62       A24   ACC   24   12   −0.672   0.92482   −1.76   0.344669   8.6553   0.5546       O   GLY 1   141       2.663       5.67       8.586       O   SER 2   157       2.57       5.524       10.215       O   THR 3   145       2.691       4.785       10.423       O   ILE 4   141       3.141       4.744       10.048       O   GLY 5   106       2.669       4.9       10.086       O   SER 6   135       2.664       4.979       10.231       O   ASP 7   148       2.413       6.773       9.962       O   SER 8   123       3.033       5.584       9.704       O   SER 9   157       2.652       5.344       10.012       O   GLY 10   163       3.026       4.753       10.51       O   SER 11   138       2.901       4.576       10.07       O   GLY 12   132       3.503       4.256       10.366       A32   ACC   32   12   2.8272   0.30273   5.1573   0.670541   10.018   0.502       OG   SER 1   142       1.908       7.501       12.689       OG   SER 2   158       1.217       8.135       13.294       OG   SER 3   146       1.984       7.724       13.283       OG   SER 4   142       2.278       7.462       12.615       OG   SER 5   107       1.06       7.551       13.088       OG   SER 8   124       2.726       8.12       13.565       OG   SER 9   158       1.901       8.072       13.351       OG   SER 10   164       1.664       7.735       13.227       OG   SER 11   139       1.857       7.578       13.136       A34   ACC   34   9   1.8439   0.50418   7.7642   0.274322   13.139   0.30794       OH   TYR 1   155       −0.171       5.291       14.251       OH   TYR 2   171       −0.291       4.635       13.936       OH   TYR 3   159       0.016       5.509       14.332       OH   TYR 4   155       0.03       4.468       13.891       OH   TYR 5   136       −0.098       3.379       13.966       OH   TYR 6   149       −0.376       4.379       13.778       OH   TYR 8   149       0.166       4.681       13.768       OH   TYR 9   171       −0.28       4.756       13.633       OH   TYR 10   178       −0.441       4.469       14.27       OH   TYR 11   152       −0.176       4.772       13.685       OH   TYR 12   146       0.376       5.384       13.961       A36   ACC   36   12   −0.113   0.24453   4.7021   0.586493   13.952   0.24008       O   CYS 1   185       1.067       9.484       9.076       O   PRO 2   201       0.576       10.012       9.398       O   PRO 3   189       0.411       9.713       9.099       O   SER 4   184       1.319       9.083       8.553       O   PRO 5   163       2.198       10.158       9.311       O   PRO 6   179       0.756       9.916       10.316       O   ALA 7   191       0.898       10.562       9.433       O   TYR 8   177       1.702       10.131       9.844       O   PRO 10   208       1.679       9.684       9.536       O   PRO 11   182       0.511       9.318       9.88       O   PRO 12   178       2.617       9.331       9.856       A38   ACC   38   11   1.2485   0.72569   9.7629   0.441462   9.482   0.48385       O   GLY 1   186       −2.149       9.494       8.888       O   GLY 2   202       −2.874       10.159       9.066       O   GLY 3   190       −2.748       9.972       8.954       O   GLY 4   185       −2.235       9.16       8.272       O   THR 6   180       −2.406       9.993       9.592       O   GLY 7   192       −2.617       10.505       8.651       O   PHE 8   178       −1.769       10.522       10.103       O   GLY 9   200       −2.438       9.522       8.495       O   GLY 11   183       −2.476       10.303       9.636       O   THR 12   180       −3.248       11.005       7.377       A40   ACC   40   10   −2.496   0.41035   10.064   0.558296   8.9034   0.77733       O   VAL 1   188       −7.78       7.375       8.869       O   ILE 2   204       −8.015       7.969       8.848       O   ILE 3   192       −7.824       8.024       8.259       O   ILE 4   187       −8.021       7.996       9.727       O   VAL 6   182       −7.651       7.627       9.43       O   ILE 7   194       −7.928       8.273       9.726       O   LEU 9   202       −8.114       8.807       9.429       O   ILE 10   211       −7.407       7.823       8.498       O   THR 11   185       −7.996       9.162       9.469       A42   ACC   42   9   −7.86   0.22197   8.1173   0.560664   9.1394   0.53745       OG1   THR 1   190       −7.639       3.969       9.24       OG1   THR 3   194       −8.9       4.567       8.706       OG   SER 4   189       −7.82       3.618       10.069       OG1   THR 6   184       −7.838       4.124       9.427       OG1   THR 7   196       −8.489       3.692       7.941       OD1   ASN 9   204       −8.271       5.097       10.004       OG1   THR 10   213       −7.925       4.335       9.016       OG1   THR 11   187       −9.807       3.729       7.97       A44   ACC   44   8   −8.336   0.72492   4.1414   0.508189   9.0466   0.81437       OD2   ASP 3   42       −6.103       −7.068       7.363       OD2   ASP 4   36       −5.98       −7.048       7.173       OG1   THR 6   38       −6.172       −8.219       7.479       OD2   ASP 11   37       −6.23       −6.97       7.91       OD2   ASP 12   37       −6.865       −6.862       7.812       A68   ACC   68   5   −6.27   0.3454   −7.233   0.556879   7.5474   0.30836                 Donors                                                     OG   SER 1   11       −9.556       −5.885       8.172           OG   SER 2   30       −9.127       −6.766       7.066       NE   ARG 4   41       −11.43       −6.012       8.513       OG   SER 8   36       −9.85       −6.053       8.039       OG   SER 9   17       −8.437       −6.835       7.057       OG   SER 10   63       −10.95       −7.408       8.89       D5   DON   5   6   −9.892   1.12248   −6.493   0.603878   7.9562   0.75319       N   SER 1   12       −9.161       −3.738       5.795       N   LYS 2   31       −9.063       −3.703       5.456       N   ALA 3   21       −8.29       −4.331       5.081       N   SER 4   15       −8.15       −3.721       5.342       N   GLY 5   13       −7.45       −3.226       6.074       N   LYS 6   17       −8.395       −4.321       5.731       N   ILE 7   16       −9.025       −4.226       5.612       N   GLY 8   10       −7.76       −3.367       5.536       N   ARG 9   18       −8.859       −3.975       5.692       N   ARG 10   39       −8.674       −4.044       4.836       N   ARG 11   16       −8.652       −3.889       5.427       N   GLY 12   16       −8.476       −3.851       6.412       D6   DON   6   12   −8.496   0.5257   −3.866   0.346377   5.5828   0.41764       OG   SER 1   12       −9.666       −1.96       8.113       OG   SER 4   15       −9.653       −1.726       7.9       D7   DON   7   2   −9.66   0.00919   −1.843   0.165463   8.0065   0.15061       N   GLY 1   13       −8.789       −0.1       5.426       N   GLY 2   32       −9.284       −0.05       5.677       N   GLY 3   22       −8.761       −0.722       5.167       N   GLY 4   16       −8.685       −0.121       5.731       N   MET 5   14       −7.572       0.427       6.428       N   GLY 6   18       −8.768       −0.685       5.543       N   SER 7   20       −9.948       1.364       5.27       N   TYR 8   11       −8.49       0.13       6.189       N   GLY 9   19       −9.129       −0.325       6.034       N   GLY 10   40       −8.828       −0.408       5.459       N   GLY 11   17       −8.878       −0.198       5.546       N   ALA 12   17       −8.931       −0.155       6.586       D8   DON   8   12   −8.839   0.5466   −0.07   0.552142   5.7547   0.45545       N   ILE 1   14       −5.584       1.406       4.565       N   ILE 2   33       −6.262       1.734       5.106       N   ILE 3   23       −6.008       1.568       4.583       N   LEU 4   17       −5.882       1.991       5.224       N   VAL 5   15       −5.284       1.794       5.226       N   ILE 6   19       −5.843       1.286       4.804       N   ILE 7   21       −6.436       2.018       4.734       N   ILE 8   12       −6.417       2.039       4.837       N   PHE 9   20       −6.214       1.631       5.229       N   ILE 10   41       −5.852       1.601       5.016       N   LEU 11   18       −6.037       1.845       5.008       N   LEU 12   18       −6.861       1.117       4.636       D9   DON   9   12   −6.057   0.41875   1.6692   0.293883   4.914   0.25367       N   LEU 1   36       −4.861       −11.14       5.491       N   SER 2   52       −5.654       −10.93       6.923       N   ASP 3   42       −4.048       −10.76       6.515       N   ASP 4   36       −3.888       −11       6.574       N   THR 6   38       −3.943       −10.92       6.379       N   PHE 7   41       −6.508       −10.95       7.546       N   ALA 9   42       −4.253       −10.74       6.218       N   TYR 10   60       −4.488       −11.11       5.821       N   ASP 11   37       −4.55       −10.8       6.546       N   ASP 12   37       −5.596       −11.16       7.002       D11   DON   11   10   −4.779   0.8737   −10.95   0.15485   6.5015   0.58747       N   VAL 1   66       0.188       −11.57       12.02       N   LEU 2   79       −0.75       −11.93       12.873       N   ILE 3   69       0.555       −10.96       12.368       N   VAL 4   60       0.173       −11.26       12.105       N   LEU 6   61       −0.617       −11.88       13.014       N   VAL 7   65       −0.2       −12.11       11.698       N   ILE 8   59       0.203       −11.54       11.611       N   VAL 10   88       0.182       −11.52       12.416       N   VAL 11   61       0.252       −11.53       11.99       OH   TYR 12   12       0.481       −11.87       9.718       D21   DON   21   10   0.0467   0.43511   −11.62   0.342553   11.981   0.91633       OG   SER 1   142       1.908       7.501       12.689       OG   SER 2   158       1.217       8.135       13.294       OG   SER 3   146       1.984       7.724       13.283       OG   SER 4   142       2.278       7.462       12.615       OG   SER 5   107       1.06       7.551       13.088       OG   SER 8   124       2.726       8.12       13.565       OG   SER 9   158       1.901       8.072       13.351       OG   SER 10   164       1.664       7.735       13.227       OG   SER 11   139       1.857       7.578       13.136       D34   DON   34   9   1.8439   0.50418   7.7642   0.274322   13.139   0.30794       OH   TYR 1   155       −0.171       5.291       14.251       OH   TYR 2   171       −0.291       4.635       13.936       OH   TYR 3   159       0.016       5.509       14.332       OH   TYR 4   155       0.03       4.468       13.891       OH   TYR 5   136       −0.098       3.379       13.966       OH   TYR 6   149       −0.376       4.379       13.778       OH   TYR 8   149       0.166       4.681       13.768       OH   TYR 9   171       −0.28       4.756       13.633       OH   TYR 10   178       −0.441       4.469       14.27       OH   TYR 11   152       −0.176       4.772       13.685       OH   TYR 12   146       0.376       5.384       13.961       D38   DON   38   11   −0.113   0.24453   4.7021   0.586493   13.952   0.24008       NZ   LYS 1   159       2.273       1.347       12.922       NZ   LYS 2   175       2.774       1.885       12.501       NZ   LYS 3   163       2.831       1.966       12.606       NZ   LYS 4   159       2.945       1.926       11.968       NZ   LYS 5   140       2.494       0.716       12.288       NZ   LYS 6   153       2.639       1.609       12.544       NZ   LYS 7   165       1.913       2.31       11.938       NZ   LYS 8   153       2.821       1.471       12.018       NZ   LYS 9   175       2.663       1.484       12.193       NZ   LYS 10   182       2.338       1.274       12.644       NZ   LYS 11   156       2.502       1.768       12.367       NZ   LYS 12   150       1.793       0.996       12.411       D40   DON   40   12   2.4988   0.36354   1.5627   0.445563   12.367   0.3007       N   VAL 1   188       −5.575       9.076       8.69       N   ILE 2   204       −5.985       9.861       8.611       N   ILE 3   192       −5.491       9.652       7.982       N   ILE 4   187       −5.774       9.173       8.669       N   VAL 6   182       −5.726       9.411       9.22       N   ILE 7   194       −5.844       10.081       9.195       N   LEU 9   202       −5.489       9.563       8.577       N   ILE 10   211       −5.165       9.506       8.351       N   THR 11   185       −5.643       10.664       9.242       N   LEU 12   181       −4.064       9.245       8.401       D45   DON   45   10   −5.476   0.54512   9.6232   0.478163   8.6938   0.41629       OG1   THR 1   190       −7.639       3.969       9.24       OG   SER 4   189       −7.82       3.618       10.069       OG1   THR 6   184       −7.838       4.124       9.427       NZ   LYS 8   84       −7.399       3.308       11.527       ND2   ASN 9   204       −7.429       3.984       8.246       OG1   THR 10   213       −7.925       4.335       9.016       D47   DON   47   6   −7.675   0.22275   3.8897   0.368935   9.5875   1.11949                 Water                                                     O   HOH 1   525       −4.833       −1.135       6.451           O   HOH 2   46       −5.297       −1.061       6.752       O   HOH 3   3       −4.845       −1.187       6.502       O   HOH 4   516       −4.351       −0.821       6.859       O   HOH 5   437       −4.101       −1.147       6.704       O   HOH 6   10       −4.524       −1.331       6.783       O   HOH 7   309       −4.955       −0.333       5.377       O   HOH 8   2       −4.854       −1.09       6.112       O   HOH 9   12       −4.878       −1.224       6.753       W4   WAT   4   9   −4.738   0.3561   −1.037   0.298174   6.477   0.47268       O   HOH 1   536       3.343       −0.704       9.644       O   HOH 5   429       1.797       −0.842       9.926       O   HOH 6   327       3.022       −1.504       10.239       O   HOH 7   293       2.636       −0.648       9.309       W5   WAT   5   4   2.6995   0.66749   −0.925   0.394841   9.7795   0.39679       O   HOH 1   556       2.764       −1.43       12.516       O   HOH 2   24       3.482       −0.937       11.868       O   HOH 3   72       4.908       −0.703       11.31       O   HOH 4   531       3.597       −0.619       12.808       O   HOH 5   433       2.747       −2.319       13.306       O   HOH 6   24       3.505       −1.086       12.854       O   HOH 7   292       2.421       −0.63       12.788       O   HOH 8   125       2.922       −0.954       13.552       O   HOH 9   6       3.111       −0.428       14.219       W9   WAT   9   9   3.273   0.73202   −1.012   0.573841   12.802   0.86657       O   HOH 1   573       −5.99       −1.752       13.358       O   HOH 4   607       −6.095       −1.503       13.507       O   HOH 5   484       −6.117       −1.942       13.958       O   HOH 6   198       −6.206       −2.028       13.818       O   HOH 8   31       −5.979       −1.748       13.701       O   HOH 9   24       −5.657       −2       13.87       W11   WAT   11   6   −6.007   0.19132   −1.829   0.200188   13.702   0.2296                    
     [0197]               TABLE 6A                          Pharmacofamily 4 Subset                                         rmsd                   from                   family       molecule #   pdb   type   avg.               1   2CAH   catalyse ( Proteus Mirabilis )   0.18       2   8CAT   catalyse (cow)   0.18                    
     [0198]               TABLE 6B                          Polypeptide and Solvent Interactors (average coordinates)                                                 atom   residue-                                   name   mol. #   total   x   σx   y   σy   z   σz                         Acceptors                                                 A3(D4)   ACC   2   −1.117   0.36133   −3.964   0.13435   −3.882   0.27082       A6(D7)   ACC   2   −10.03   0.10889   −5.617   0.029698   1.223   0.1895       A17   ACC   2   5.454   0.08697   2.473   0.195161   −0.056   0.58973       A19(D30)   ACC   2   3.405   0.48366   1.421   0.065761   4.934   0.05586       A21   ACC   2   1.11   0.65478   −7.271   0.181726   −2.784   0.39527       A35   ACC   2   3.372       −7.545       0.205                    
     [0199]                                                               atom   residue-                                   name   mol. #   total   x   σx   y   σy   z   σz                                    Donors                                                 D4(A3)   DON   2   −1.117   0.36133   −3.964   0.13435   −3.882   0.27082       D7(A6)   DON   2   −10.03   0.10889   −5.617   0.029698   1.223   0.1895       D10   DON   2   −6.918   0.49215   −1.253   0.286378   7   0.28284       D11   DON   2   −6.419   0.19163   0.023   0.147078   5.184   0.18173       D14   DON   2   −6.153       3.824       6.584       D21   DON   2   −2.402       4.522       6.578       D22   DON   2   −2.704   0.0997   4.738   0.703571   9.015   0.19658       D26   DON   2   4.609   0.02758   2.264   0.350018   −2.894   0.51831       D30(A19)   DON   2   3.405   0.48366   1.421   0.065761   4.934   0.05586       D42   DON   2   3.907       6.034       0.45                 Waters                                                 W1   WAT   2   2.756       3.789       −1.727           W3   WAT   2   7.572       −1.978       4.115                    
     [0200]               TABLE 6C                          NAD(P) Conformer Model                                             atom name   number   x   σx   y   σy   z   σz                                                     PA   2   2.91   0.04   −2.21   0.03   5.65   0.05       O1A   2   2.72   0.06   −3.30   0.15   6.64   0.05       O2A   2   3.84   0.02   −1.14   0.13   6.03   0.21       O5′A   2   1.43   0.11   −1.58   0.12   5.49   0.10       C5′A   2   0.37   0.04   −2.46   0.22   4.99   0.04       C4′A   2   −0.65   0.05   −1.65   0.13   4.29   0.00       O4′A   2   −1.84   0.18   −2.41   0.04   4.08   0.03       C3′A   2   −1.09   0.10   −0.66   0.26   5.21   0.33       O3′A   2   −0.77   0.41   0.64   0.09   5.13   0.06       C2′A   2   −2.37   0.16   −1.05   0.21   5.80   0.03       O2′A   2   −3.24   0.42   0.04   0.54   6.17   0.19       C1′A   2   −3.00   0.12   −1.63   0.23   4.60   0.08       N9A   2   −4.14   0.04   −2.49   0.13   4.54   0.09       C8A   2   −4.58   0.08   −3.42   0.00   5.41   0.04       N7A   2   −5.62   0.12   −4.11   0.07   5.01   0.00       C5A   2   −5.86   0.04   −3.62   0.02   3.74   0.06       C6A   2   −6.85   0.05   −3.94   0.05   2.77   0.07       N6A   2   −7.79   0.12   −4.87   0.11   2.95   0.01       N1A   2   −6.82   0.06   −3.25   0.04   1.61   0.11       C2A   2   −5.88   0.13   −2.29   0.16   1.45   0.15       N3A   2   −4.93   0.16   −1.91   0.18   2.28   0.15       C4A   2   −4.98   0.06   −2.62   0.08   3.43   0.10       O3   2   3.16   0.09   −2.77   0.20   4.19   0.05       PN   2   4.13   0.03   −2.43   0.03   3.00   0.01       O1N   2   5.29   0.18   −3.36   0.17   3.00   0.07       O2N   2   4.47   0.33   −1.02   0.09   2.89   0.03       O5′N   2   3.25   0.11   −2.85   0.18   1.72   0.04       C5′N   2   2.89   0.14   −4.22   0.12   1.54   0.19       C4′N   2   1.52   0.19   −4.31   0.05   0.90   0.20       O4′N   2   0.53   0.15   −3.57   0.13   1.66   0.23       C3′N   2   1.50   0.08   −3.79   0.10   −0.56   0.22       O3′N   2   1.58   0.07   −4.98   0.12   −1.40   0.15       C2′N   2   0.05   0.15   −3.27   0.00   −0.68   0.16       O2′N   2   −0.79   0.07   −4.25   0.19   −1.31   0.32       C1′N   2   −0.40   0.12   −3.01   0.11   0.75   0.17       N1N   2   −0.50   0.05   −1.58   0.13   0.98   0.02       C2N   2   0.63   0.01   −0.80   0.12   0.85   0.05       C3N   2   0.57   0.04   0.56   0.14   1.01   0.11       C7N   2   1.78   0.11   1.45   0.05   0.85   0.11       O7N   2   1.68   0.14   2.77   0.09   0.94   0.20       N7N   2   2.98   0.14   0.95   0.01   0.59   0.03       C4N   2   −0.64   0.03   1.18   0.17   1.31   0.31       C5N   2   −1.74   0.06   0.35   0.27   1.46   0.35       C6N   2   −1.71   0.03   −1.02   0.24   1.31   0.20       P2′   2   −3.70   0.19   0.63   0.15   7.56   0.08       OP1   2   −3.38   0.20   −0.29   0.13   8.64   0.19       OP2   2   −5.04   0.42   1.06   0.50   7.59   0.15       OP3   2   −2.80   0.72   1.78   0.50   7.64   0.13                    
     [0201]               TABLE 6D                          Polypeptide and Solvent Interactors                                                         residue-                                       atom name   mol. #   residue #   total   x   σx   y   σy   z   σz                         Acceptors                                                     NE2   HIS 1   173       −1.37       −4.06       −3.69           NE2   HIS 2   193       −0.86       −3.87       −4.07       A3   ACC   3   2   −1.12   0.36   −3.96   0.13   −3.88   0.27       OG   SER 1   180       −10.10       −5.60       1.09       OG   SER 2   200       −9.95       −5.64       1.36       A6   ACC   6   2   −10.03   0.11   −5.62   0.03   1.22   0.19       O   TRP 1   282       5.52       2.34       −0.47       O   TRP 2   302       5.39       2.61       0.36       A17   ACC   17   2   5.45   0.09   2.47   0.20   −0.06   0.59       ND1   HIS 1   284       3.06       1.47       4.97       ND1   HIS 2   304       3.75       1.38       4.89       A19   ACC   19   2   3.41   0.48   1.42   0.07   4.93   0.06       O   GLN 1   421       0.65       −7.40       −2.50       O   GLN 2   441       1.57       −7.14       −3.06       A21   ACC   21   2   1.11   0.65   −7.27   0.18   −2.78   0.40       OG1   THR 2   444       3.37       −7.55       0.21       A35   ACC   35   2   3.37       −7.55       0.21                 Donors                                                     NE2   HIS 1   173       −1.37       −4.06       −3.69           NE2   HIS 2   193       −0.86       −3.87       −4.07       D4   DON   4   2   −1.12   0.36   −3.96   0.13   −3.88   0.27       OG   SER 1   180       −10.10       −5.60       1.09       OG   SER 2   200       −9.95       −5.64       1.36       D7   DON   7   2   −10.03   0.11   −5.62   0.03   1.22   0.19       NH1   ARG 1   182       −7.27       −1.05       6.80       NH1   ARG 2   202       −6.57       −1.46       7.20       D10   DON   10   2   −6.92   0.49   −1.25   0.29   7.00   0.28       NH2   ARG 1   182       −6.28       0.13       5.06       NH2   ARG 2   202       −6.56       −0.08       5.31       D11   DON   11   2   −6.42   0.19   0.02   0.15   5.18   0.18       NE2   HIS 1   192       −6.15       3.82       6.58       D14   DON   14   2   −6.15       3.82       6.58       NH1   ARG 1   216       −2.40       4.52       6.58       D21   DON   21   2   −2.40       4.52       6.58       NH2   ARG 1   216       −2.78       4.24       8.88       NZ   LYS 2   236       −2.63       5.24       9.15       D22   DON   22   2   −2.70   0.10   4.74   0.70   9.02   0.20       N   TRP 1   282       4.59       2.02       −3.26       N   TRP 2   302       4.63       2.51       −2.53       D26   DON   26   2   4.61   0.03   2.26   0.35   −2.89   0.52       ND1   HIS 1   284       3.06       1.47       4.97       ND1   HIS 2   304       3.75       1.38       4.89       D30   DON   30   2   3.41   0.48   1.42   0.07   4.93   0.06       NE2   GLN 2   281       3.91       6.03       0.45       D42   DON   42   2   3.91       6.03       0.45                 Waters                                                     O   HOH 1   10       2.76       3.79       −1.73           W1   WAT   1   2   2.76       3.79       −1.73       O   HOH 1   12       7.57       −1.98       4.12       W3   WAT   3   2   7.57       −1.98       4.12                    
     [0202]               TABLE 7A                          Pharmacofamily 5 Subset                                         RMSD                   from                   Family       Molecule #   pdb   type   Avg.               1   1A80   2,5-Diketo-D-   0.21               Gluconic Acid               Reductase               (Cornybacterium       2   1AFS   3-a-Hydroxysteroid Dehydrogenase (rat)   0.66       3   1FRB   Aldo-Keto Reductase (mouse)   0.55       4   1ADS   Aldose Reductase (human)   0.55       5   1AH0   Aldose Reductase (pig)   0.56                    
     [0203]               TABLE 7B                          Polypeptide and Solvent Interactors (average coordinates)                                                 atom   residue-                                   name   mol. #   total   x   σx   y   σy   z   σz                         Acceptors                                                 A3   ACC   5   −0.31   0.38   8.08   0.84   −3.93   0.51       A5   ACC   5   −7.54   0.31   10.00   0.16   0.36   0.24       A8(D6)   ACC   5   −3.86   0.33   10.11   0.12   2.13   0.21       A11(D11)   ACC   5   −3.42   0.36   10.75   0.31   6.12   0.36       A14(D15)   ACC   5   −7.65   0.42   8.35   0.28   7.93   0.19       A18   ACC   5   −8.07   0.25   7.90   0.12   3.55   0.09       A32(D35)   ACC   5   −3.37   0.49   3.38   0.29   −11.88   0.27       A37   ACC   5   −6.70   0.49   −3.63   0.36   −15.32   0.27       A38   ACC   5   −7.25   0.30   −4.35   0.17   −13.39   0.20       A40   ACC   4   −8.26   0.22   −0.78   0.09   −10.85   0.30       A42(D21)   ACC   4   −4.11   0.29   3.97   0.06   7.45   0.05       A43(D49)   ACC   4   −3.07   0.46   1.67   0.40   1.87   0.38       A55(D65)   ACC   3   0.11   0.37   1.66   0.18   −0.35   0.22       A58   ACC   3   1.32   0.18   2.39   0.11   −4.18   0.31       A59   ACC   3   1.96   0.22   4.01   0.11   −5.47   0.31                 Donors                                                 D2   DON   5   −4.83   0.41   9.93   0.42   −4.13   0.06       D3   DON   5   −2.29   0.33   9.76   0.48   −2.96   0.18       D6(A8)   DON   5   −3.86   0.33   10.11   0.12   2.13   0.21       D11(A11)   DON   5   −3.42   0.36   10.75   0.31   6.12   0.36       D15(A14)   DON   5   −7.65   0.42   8.35   0.28   7.93   0.19       D17   DON   5   −4.88   0.29   7.13   0.34   9.26   0.08       D21(A42)   DON   5   −4.42   0.74   4.02   0.11   7.28   0.39       D22   DON   5   −5.81   0.30   1.79   0.28   0.94   0.10       D24   DON   5   −5.85   0.17   −2.29   0.15   −2.39   0.10       D26   DON   5   −1.59   0.17   −1.52   0.26   −1.17   0.14       D27   DON   1   −0.90   —   2.47   —   1.79   —       D32   DON   5   −5.76   0.30   3.99   0.12   −5.84   0.34       D35(A32)   DON   5   −3.37   0.49   3.38   0.29   −11.88   0.27       D36   DON   5   −1.89   0.69   6.00   0.37   −11.25   0.14       D43   DON   5   0.35   0.44   0.04   0.54   −12.44   0.04       D47   DON   4   −7.47   0.24   1.06   0.13   −9.91   0.26       D49(A43)   DON   4   −3.07   0.46   1.67   0.40   1.87   0.38       D64   DON   3   0.37   0.27   4.92   0.07   −3.02   0.15       D65(A55)   DON   3   0.11   0.37   1.66   0.18   −0.35   0.22                 Waters                                                 W1   WAT   4   0.62   0.21   −3.17   0.55   −8.81   0.66       W9   WAT   4   2.90   0.30   3.03   0.33   −8.84   0.37                    
     [0204]               TABLE 7C                          NAD(P) Conformer Model                                             atom name   total   x   σx   y   σy   z   σz                                                     PA   5   −3.59   0.07   1.15   0.06   −3.16   0.09       O1A   5   −3.91   0.07   −0.06   0.08   −2.37   0.06       O2A   5   −4.70   0.10   1.87   0.11   −3.82   0.09       O5′A   5   −2.52   0.10   0.72   0.06   −4.25   0.09       C5′A   5   −1.97   0.11   1.62   0.06   −5.21   0.09       C4′A   5   −1.00   0.13   0.82   0.07   −6.06   0.07       O4′A   5   −1.74   0.17   −0.16   0.08   −6.80   0.06       C3′A   5   −0.24   0.20   1.65   0.08   −7.07   0.11       O3′A   5   1.09   0.17   1.16   0.21   −7.14   0.19       C2′A   5   −0.96   0.21   1.42   0.12   −8.38   0.08       O2′A   5   −0.03   0.25   1.44   0.24   −9.46   0.12       C1′A   5   −1.49   0.16   0.01   0.09   −8.20   0.07       N9A   5   −2.74   0.16   −0.23   0.11   −8.94   0.08       C8A   5   −3.87   0.15   0.51   0.05   −9.04   0.13       N7A   5   −4.77   0.16   −0.07   0.05   −9.80   0.19       C5A   5   −4.20   0.14   −1.23   0.09   −10.20   0.13       C6A   5   −4.67   0.20   −2.26   0.14   −11.02   0.14       N6A   5   −5.88   0.24   −2.27   0.19   −11.55   0.20       N1A   5   −3.84   0.23   −3.30   0.17   −11.24   0.14       C2A   5   −2.64   0.22   −3.33   0.19   −10.69   0.18       N3A   5   −2.13   0.23   −2.39   0.17   −9.90   0.15       C4A   5   −2.94   0.14   −1.35   0.12   −9.67   0.08       O3   5   −2.67   0.10   2.02   0.11   −2.19   0.13       PN   5   −2.64   0.33   3.48   0.09   −1.61   0.18       O2N   5   −1.78   0.43   3.39   0.25   −0.42   0.27       O1N   5   −2.28   0.39   4.43   0.23   −2.64   0.37       O5′N   5   −4.08   0.45   3.75   0.33   −1.10   0.12       C5′N   5   −5.08   0.40   4.38   0.23   −1.89   0.10       C4′N   5   −5.43   0.23   5.74   0.13   −1.36   0.03       O4′N   5   −5.93   0.16   5.65   0.12   −0.02   0.04       C3′N   5   −4.26   0.18   6.68   0.23   −1.23   0.10       O3′N   5   −3.85   0.24   7.22   0.37   −2.47   0.14       C2′N   5   −4.83   0.19   7.72   0.11   −0.32   0.12       O2′N   5   −5.69   0.24   8.58   0.11   −1.05   0.14       C1′N   5   −5.61   0.09   6.86   0.10   0.66   0.03       N1N   5   −4.82   0.08   6.56   0.06   1.86   0.06       C2N   5   −5.21   0.09   7.16   0.08   3.04   0.07       C3N   5   −4.46   0.11   6.94   0.05   4.21   0.09       C7N   5   −4.88   0.17   7.54   0.12   5.51   0.09       O7N   5   −4.17   0.19   7.45   0.25   6.50   0.12       N7N   5   −6.04   0.21   8.19   0.19   5.56   0.07       C4N   5   −3.34   0.13   6.14   0.07   4.16   0.09       C5N   5   −2.95   0.14   5.55   0.14   2.98   0.11       C6N   5   −3.70   0.10   5.76   0.14   1.84   0.10       P2′   5   −0.06   0.34   2.60   0.41   −10.53   0.12       OP1   5   −0.57   0.66   3.20   0.94   −10.55   0.97       OP2   5   0.89   1.15   2.72   0.92   −10.83   0.65       OP3   5   −0.55   0.81   2.71   0.77   −11.09   0.69                    
     [0205]               TABLE 7D                          Polypeptide and Solvent Interactors                                                         residue-                                       atom name   mol. #   residue #   total   x   σx   y   σy   z   σz                         Acceptors                                                     O   PHE 1   22       −0.22       7.917       −3.902           O   THR 2   24       −0.117       9.552       −4.723       O   TRP 3   20       −0.078       7.638       −3.451       O   TRP 4   20       −0.136       7.449       −3.508       O   TRP 5   20       −0.979       7.848       −4.071       A3   ACC   3   5   −0.306   0.37978   8.0808   0.842719   −3.931   0.51406       OD1   ASP 1   45       −7.465       10.181       0.624       OD2   ASP 2   50       −7.821       9.947       0.608       OD2   ASP 3   43       −7.26       10.05       0.226       OD2   ASP 4   43       −7.257       10.064       0.178       OD2   ASP 5   43       −7.906       9.75       0.15       A5   ACC   5   5   −7.542   0.30701   9.9984   0.161751   0.3572   0.23788       OH   TYR 1   50       −3.489       9.992       2.109       OH   TYR 2   55       −4.193       10.25       2.441       OH   TYR 3   48       −3.749       9.978       2.218       OH   TYR 4   48       −3.652       10.133       1.976       OH   TYR 5   48       −4.239       10.209       1.899       A8   ACC   8   5   −3.864   0.33454   10.112   0.123743   2.1286   0.21329       NE2   HIS 1   108       −3.007       10.311       6.445       NE2   HIS 2   117       −3.912       10.677       6.566       NE2   HIS 3   110       −3.39       11.167       5.845       NE2   HIS 4   110       −3.153       10.889       5.871       NE2   HIS 5   110       −3.636       10.73       5.849       A11   ACC   11   5   −3.42   0.36451   10.755   0.312868   6.1152   0.35899       OG   SER 1   139       −7.14       8.138       8.261       OG   SER 2   166       −8.27       7.971       7.92       OG   SER 3   159       −7.772       8.621       7.778       OG   SER 4   159       −7.65       8.495       7.82       OG   SER 5   159       −7.437       8.529       7.856       A14   ACC   14   5   −7.654   0.41973   8.3508   0.280664   7.927   0.19384       OE1   GLN 1   161       −7.73       7.828       3.644       OE1   GLN 2   190       −8.407       7.736       3.471       OE1   GLN 3   183       −8.012       8.025       3.461       OE1   GLN 4   183       −8.028       7.965       3.514       OE1   GLN 5   183       −8.175       7.938       3.638       A18   ACC   18   5   −8.07   0.24765   7.8984   0.1155   3.5456   0.08936       OG   SER 1   233       −2.688       3.039       −11.94       OG   SER 2   271       −3.273       3.123       −12.31       OG   SER 3   263       −3.404       3.664       −11.79       OG   SER 4   263       −3.447       3.654       −11.8       OG   SER 5   263       −4.061       3.397       −11.59       A32   ACC   32   5   −3.375   0.48964   3.3754   0.290794   −11.88   0.27029       OE1   GLU 1   241       −6.654       −3.242       −15.12       OE1   GLU 2   279       −6.05       −4.113       −15.74       OE1   GLU 3   271       −6.813       −3.347       −15.07       OE1   GLU 4   271       −6.579       −3.598       −15.29       OE1   GLU 5   271       −7.419       −3.871       −15.4       A37   ACC   37   5   −6.703   0.49217   −3.634   0.361573   −15.32   0.26598       OE2   GLU 1   241       −7.599       −4.219       −13.37       OE2   GLU 2   279       −6.79       −4.645       −13.74       OE2   GLU 3   271       −7.422       −4.351       −13.25       OE2   GLU 4   271       −7.243       −4.266       −13.32       OE2   GLU 5   271       −7.176       −4.27       −13.3       A38   ACC   38   5   −7.246   0.30349   −4.35   0.171495   −13.39   0.19848       OD1   ASN 1   242       −8.167       −0.847       −11.28       OD1   ASN 3   272       −8.198       −0.802       −10.63       OD1   ASN 4   272       −8.082       −0.656       −10.87       OD1   ASN 5   272       −8.588       −0.828       −10.63       A40   ACC   40   4   −8.259   0.22491   −0.783   0.086815   −10.85   0.30469       OH   TYR 2   216       −4.48       3.904       7.523       OH   TYR 3   209       −4.079       3.966       7.44       OH   TYR 4   209       −4.093       4.039       7.418       OH   TYR 5   209       −3.784       3.971       7.417       A42   ACC   42   4   −4.109   0.28544   3.97   0.055178   7.4495   0.05014       SG   CYS 2   217       −2.381       1.081       2.263       OG   SER 3   210       −3.198       1.802       1.827       OG   SER 4   210       −3.328       1.843       2.013       OG   SER 5   210       −3.366       1.953       1.365       A43   ACC   43   4   −3.068   0.46378   1.6698   0.397644   1.867   0.37936       OG   SER 3   214       0.302       1.569       −0.171       OG   SER 4   214       0.348       1.533       −0.286       OG   SER 5   214       −0.31       1.864       −0.589       A55   ACC   55   3   0.1133   0.36734   1.6553   0.181605   −0.349   0.21593       OD1   ASP 3   216       1.445       2.279       −4.029       OD1   ASP 4   216       1.393       2.409       −3.965       OD1   ASP 5   216       1.107       2.494       −4.537       A58   ACC   58   3   1.315   0.182   2.394   0.108282   −4.177   0.31341       OD2   ASP 3   216       2.06       3.9       −5.346       OD2   ASP 4   216       2.112       3.991       −5.233       OD2   ASP 5   216       1.712       4.127       −5.826       A59   ACC   59   3   1.9613   0.21749   4.006   0.114241   −5.468   0.31486                 Donors                                                     N   VAL 1   21       −4.573       10.277       −4.214           N   THR 2   23       −4.955       10.482       −4.051       N   THR 3   19       −4.601       9.587       −4.125       N   THR 4   19       −4.539       9.637       −4.107       N   THR 5   19       −5.495       9.654       −4.137       D2   DON   2   5   −4.833   0.40651   9.9274   0.419748   −4.127   0.05884       N   PHE 1   22       −2.163       9.689       −2.98       N   THR 2   24       −2.234       10.595       −3.208       N   TRP 3   20       −2.126       9.537       −2.765       N   TRP 4   20       −2.061       9.403       −2.815       N   TRP 5   20       −2.861       9.571       −3.033       D3   DON   3   5   −2.289   0.32582   9.759   0.47832   −2.96   0.17768       OH   TYR 1   50       −3.489       9.992       2.109       OH   TYR 2   55       −4.193       10.25       2.441       OH   TYR 3   48       −3.749       9.978       2.218       OH   TYR 4   48       −3.652       10.133       1.976       OH   TYR 5   48       −4.239       10.209       1.899       D6   DON   6   5   −3.864   0.33454   10.112   0.123743   2.1286   0.21329       NE2   HIS 1   108       −3.007       10.311       6.445       NE2   HIS 2   117       −3.912       10.677       6.566       NE2   HIS 3   110       −3.39       11.167       5.845       NE2   HIS 4   110       −3.153       10.889       5.871       NE2   HIS 5   110       −3.636       10.73       5.849       D11   DON   11   5   −3.42   0.36451   10.755   0.312868   6.1152   0.35899       OG   SER 1   139       −7.14       8.138       8.261       OG   SER 2   166       −8.27       7.971       7.92       OG   SER 3   159       −7.772       8.621       7.778       OG   SER 4   159       −7.65       8.495       7.82       OG   SER 5   159       −7.437       8.529       7.856       D15   DON   15   5   −7.654   0.41973   8.3508   0.280664   7.927   0.19384       ND2   ASN 1   140       −4.533       6.58       9.266       ND2   ASN 2   167       −5.286       7.047       9.369       ND2   ASN 3   160       −4.994       7.442       9.225       ND2   ASN 4   160       −4.894       7.259       9.278       ND2   ASN 5   160       −4.669       7.311       9.151       D17   DON   17   5   −4.875   0.29276   7.1278   0.33768   9.2578   0.07957       NE1   TRP 1   187       −5.659       4.197       6.593       OH   TYR 2   216       −4.48       3.904       7.523       OH   TYR 3   209       −4.079       3.966       7.44       OH   TYR 4   209       −4.093       4.039       7.418       OH   TYR 5   209       −3.784       3.971       7.417       D21   DON   21   5   −4.419   0.73594   4.0154   0.112202   7.2782   0.38549       N   GLY 1   188       −5.543       1.806       1.07       N   CYS 2   217       −5.457       1.307       0.834       N   SER 3   210       −5.913       2.008       0.883       N   SER 4   210       −5.995       1.926       1.01       N   SER 5   210       −6.138       1.889       0.879       D22   DON   22   5   −5.809   0.29509   1.7872   0.278086   0.9352   0.09986       N   LEU 1   190       −6.122       −2.167       −2.319       N   LEU 2   219       −5.697       −2.431       −2.521       N   LEU 3   212       −5.848       −2.116       −2.486       N   LEU 4   212       −5.837       −2.313       −2.318       N   LEU 5   212       −5.738       −2.444       −2.315       D24   DON   24   5   −5.848   0.1659   −2.294   0.149535   −2.392   0.10273       N   GLN 1   192       −1.835       −1.942       −1.288       N   SER 2   221       −1.633       −1.501       −0.943       N   SER 3   214       −1.557       −1.387       −1.269       N   SER 4   214       −1.543       −1.524       −1.135       N   SER 5   214       −1.368       −1.233       −1.228       D26   DON   26   5   −1.587   0.16913   −1.517   0.263858   −1.173   0.14125       NE2   GLN 1   192       −0.903       2.473       1.785       D27   DON   27   1   −0.903       2.473       1.785       N   LYS 1   232       −5.402       4.166       −6.054       N   ARG 2   270       −5.952       3.855       −6.343       N   LYS 3   262       −5.685       4.007       −5.639       N   LYS 4   262       −5.623       3.992       −5.582       N   LYS 5   262       −6.162       3.913       −5.584       D32   DON   32   5   −5.765   0.29619   3.9866   0.117649   −5.84   0.34326       OG   SER 1   233       −2.688       3.039       −11.94       OG   SER 2   271       −3.273       3.123       −12.31       OG   SER 3   263       −3.404       3.664       −11.79       OG   SER 4   263       −3.447       3.654       −11.8       OG   SER 5   263       −4.061       3.397       −11.59       D35   DON   35   5   −3.375   0.48964   3.3754   0.290794   −11.88   0.27029       N   VAL 1   234       −1.14       5.556       −11.43       N   PHE 2   272       −1.614       5.656       −11.37       N   VAL 3   264       −1.81       6.206       −11.19       N   VAL 4   264       −1.882       6.219       −11.12       N   VAL 5   264       −3.012       6.373       −11.15       D36   DON   36   5   −1.892   0.68993   6.002   0.369113   −11.25   0.13745       NH1   ARG 1   238       0.069       −0.686       −12       NH2   ARG 2   276       1.098       0.722       −13.92       NH1   ARG 3   268       0.415       0.209       −12.73       NH1   ARG 4   268       0.039       −0.27       −11.5       NH2   ARG 5   268       0.142       0.24       −12.05       D43   DON   43   4   0.3526   0.44234   0.043   0.537777   −12.44   0.93623       ND2   ASN 1   242       −7.301       0.978       −10.22       ND2   ASN 3   272       −7.385       1.094       −9.791       ND2   ASN 4   272       −7.367       1.218       −10.01       ND2   ASN 5   272       −7.832       0.939       −9.618       D47   DON   47   4   −7.471   0.2432   1.0573   0.125771   −9.91   0.26174       SG   CYS 2   217       −2.381       1.081       2.263       OG   SER 3   210       −3.198       1.802       1.827       OG   SER 4   210       −3.328       1.843       2.013       OG   SER 5   210       −3.366       1.953       1.365       D49   DON   49   4   −3.068   0.46378   1.6698   0.397644   1.867   0.37936       NZ   LYS 3   21       0.563       4.894       −2.898       NZ   LYS 4   21       0.487       4.857       −2.975       NZ   LYS 5   21       0.06       4.999       −3.187       D64   DON   64   3   0.37   0.27114   4.9167   0.073664   −3.02   0.14966       OG   SER 3   214       0.302       1.569       −0.171       OG   SER 4   214       0.348       1.533       −0.286       OG   SER 5   214       −0.31       1.864       −0.589       D65   DON   65   3   0.1133   0.36734   1.6553   0.181605   −0.349   0.21593                 Waters                                                     O   HOH 1   396       3.263       2.796       −9.047           O   HOH 3   536       3.02       2.698       −8.645       O   HOH 4   484       2.686       3.261       −8.435       O   HOH 5   586       2.613       3.35       −9.237       W9   WAT   9   4   2.895   0.30235   3.026   0.326948   −8.841   0.36629       O   HOH 1   307       0.306       −3.84       −7.869       O   HOH 3   731       0.694       −3.294       −8.887       O   HOH 4   485       0.782       −3.008       −9.378       O   HOH 5   483       0.686       −2.519       −9.123       W1   WAT   1   4   0.617   0.21185   −3.165   0.552036   −8.814   0.66129                    
     [0206]               TABLE 8A                          Pharmacofamily 6 Subset                                         RMSD                   from                   Family       Molecule #   pdb   type   Avg.                                     1   1AI9   Dihydrofolate Reductase   0.49               ( candida albicans )       2   1DAJ   DHFR ( pneumocystis carinii )   0.8       3   1DLR   DHFR (human)   0.6       4   1DR1   DHFR (chicken)   0.83       5   1DRE   DHFR ( E. coli )   0.91       6   3DFR   DHFR ( Lactobacillus casei )   0.84                    
     [0207]               TABLE 8B                          Polypeptide and Solvent Interactors (average coordinates)                                                 atom name   Name   total   x   σx   Y   σy   z   σz                         Acceptors                                                 A2   ACC   6   −7.76   0.34   9.50   0.60   15.24   0.31       A3   ACC   6   −3.33   0.36   9.00   0.28   13.41   0.29       A7   ACC   6   4.38   0.42   8.51   0.59   14.79   0.44       A8   ACC   5   0.64   0.44   10.67   0.55   12.99   0.29       A22   ACC   5   1.78   0.52   −12.11   0.61   17.27   0.35       A29   ACC   3   1.38   0.22   −3.65   0.98   10.30   0.42       A45(D53)   ACC   5   7.52   0.32   −6.82   0.15   17.60   0.52       A64   ACC   1   3.88       7.64       10.73                 Donors                                                 D2   DON   6   −8.77   0.24   8.47   0.48   17.58   0.39       D5   DON   6   0.31   0.46   10.32   0.28   10.41   0.31       D7   DON   6   4.49   0.64   8.48   0.37   11.28   0.47       D8   DON   6   3.29   0.49   9.75   0.37   13.31   0.28       D10   DON   6   0.75   0.68   11.75   0.20   14.90   0.31       D13   DON   6   0.42   0.31   −1.68   0.29   18.99   0.21       D14   DON   6   3.77   0.31   −2.26   0.30   17.84   0.28       D15   DON   3   9.09   0.30   −3.80   0.34   14.68   0.76       D18   DON   6   4.89   0.37   0.01   0.38   16.50   0.32       D19   DON   3   5.76   0.34   −0.45   1.23   11.73   0.54       D20   DON   6   3.21   0.48   2.15   0.27   17.41   0.31       D24   DON   6   8.21   0.50   −9.32   0.64   16.12   0.77       D25   DON   6   5.73   0.39   −9.28   0.30   16.15   0.47       D27   DON   2   4.63   0.21   −8.88   0.26   11.81   0.22       D35   DON   6   −1.87   0.34   0.75   0.49   16.42   0.33       D37   DON   6   −2.91   0.56   −1.48   0.83   11.81   0.33       D38   DON   6   −3.30   0.47   −3.07   0.64   14.06   0.39       D40   DON   5   −6.32   0.26   3.86   0.48   17.78   0.67       D53(A45)   DON   5   7.52   0.32   −6.82   0.15   17.60   0.52       D58   DON   2   4.59   0.01   4.70   0.53   10.76   0.38                 Waters                                                 W5   WAT   3   3.12   0.69   4.35   0.33   10.23   0.39       W7   WAT   3   2.33   0.11   6.97   0.14   10.21   0.07       W9   WAT   2   1.38   0.94   3.27   0.01   9.07   0.57       W10   WAT   3   −2.58   0.27   −11.63   0.89   15.29   0.33                    
     [0208]               TABLE 8C                          NAD(P) Conformer Model                                             atom name   total   x   σx   y   σy   z   σz                                                     PA   6   1.05   0.24   −0.17   0.19   14.67   0.19       O1A   6   1.19   0.24   0.64   0.25   15.88   0.23       O2A   6   −0.20   0.24   −0.90   0.28   14.47   0.18       O5′A   6   2.35   0.21   −1.13   0.14   14.56   0.24       C5′A   6   2.40   0.23   −2.23   0.10   13.62   0.23       C4′A   6   3.42   0.23   −3.27   0.14   14.17   0.18       O4′A   6   2.79   0.36   −3.93   0.29   15.07   0.24       C3′A   6   3.64   0.12   −4.36   0.13   13.07   0.19       O3′A   6   4.70   0.13   −3.76   0.25   12.26   0.24       C2′A   6   4.06   0.05   −5.51   0.17   14.00   0.26       O2′A   6   5.31   0.06   −5.32   0.34   14.57   0.28       C1′A   6   3.05   0.11   −5.32   0.22   15.11   0.22       N9A   6   1.81   0.09   −5.96   0.35   14.84   0.21       C8A   6   0.76   0.17   −5.40   0.56   14.27   0.47       N7A   6   −0.27   0.17   −6.16   0.65   14.17   0.44       C5A   6   0.21   0.15   −7.35   0.53   14.68   0.21       C6A   6   −0.44   0.24   −8.68   0.51   14.89   0.32       N6A   6   −1.69   0.28   −8.92   0.67   14.53   0.44       N1A   6   0.29   0.35   −9.56   0.36   15.44   0.49       C2A   6   1.54   0.34   −9.19   0.25   15.79   0.52       N3A   6   2.22   0.25   −8.09   0.22   15.65   0.34       C4A   6   1.45   0.13   −7.18   0.35   15.09   0.07       O3   6   1.42   0.24   0.75   0.10   13.47   0.20       PN   6   0.72   0.34   1.45   0.19   12.25   0.14       O1N   6   1.73   0.45   1.89   0.29   11.31   0.22       O2N   6   −0.36   0.53   0.71   0.34   11.74   0.15       O5′N   6   0.22   0.15   2.75   0.17   12.92   0.26       C5′N   6   1.01   0.12   3.77   0.28   13.48   0.39       C4′N   6   0.38   0.25   5.08   0.27   13.02   0.22       O4′N   6   −0.91   0.16   5.18   0.29   13.67   0.13       C3′N   6   1.12   0.29   6.33   0.23   13.52   0.32       O3′N   6   1.00   0.36   7.39   0.27   12.63   0.36       C2′N   6   0.45   0.21   6.61   0.24   14.87   0.28       O2′N   6   0.66   0.31   7.95   0.27   15.21   0.40       C1′N   6   −0.96   0.21   6.30   0.20   14.54   0.23       N1N   6   −1.94   0.08   6.13   0.21   15.69   0.16       C2N   6   −3.04   0.10   6.97   0.25   15.83   0.15       C3N   6   −3.94   0.11   6.79   0.28   16.76   0.16       C7N   6   −5.03   0.17   7.76   0.42   16.79   0.23       O7N   6   −5.87   0.22   7.55   0.50   17.62   0.42       N7N   6   −5.15   0.38   8.68   0.43   15.88   0.20       C4N   6   −3.80   0.33   5.71   0.33   17.78   0.25       C5N   6   −2.57   0.33   4.91   0.28   17.56   0.23       C6N   6   −1.72   0.21   5.11   0.17   16.58   0.19       P2′   6   6.67   0.14   −6.07   0.47   14.05   0.35       OP1   6   6.95   0.63   −6.04   0.74   14.07   1.55       OP2   6   6.45   0.52   −7.18   0.71   13.88   0.88       OP3   6   7.41   0.41   −5.33   0.70   13.79   0.83                    
     [0209]               TABLE 8D                          Polypeptide and Solvent Interactors                                                         residue-                                       atom name   mol. #   residue #   total   x   σx   y   σy   z   σz                         Acceptors                                                     O   ALA 1   11       −8.25       9.15       15.70           O   ALA 2   12       −7.62       9.56       15.25       O   ALA 3   9       −7.84       8.91       15.02       O   ALA 4   9       −8.02       9.04       15.08       O   ALA 5   7       −7.34       10.51       14.88       O   ALA 6   6       −7.50       9.83       15.51       A2   ACC   2   6   −7.76   0.34   9.50   0.60   15.24   0.31       O   ILE 1   19       −3.73       9.16       13.34       O   ILE 2   19       −3.77       8.82       13.73       O   ILE 3   16       −3.18       8.72       13.35       O   ILE 4   16       −3.34       8.72       13.44       O   ILE 5   14       −2.92       9.18       12.93       O   ILE 6   13       −3.03       9.39       13.70       A3   ACC   3   6   −3.33   0.36   9.00   0.28   13.41   0.29       O   GLY 1   23       3.59       8.74       14.29       O   ASN 2   23       4.73       8.14       14.25       O   GLY 3   20       4.28       9.37       15.16       O   GLY 4   20       4.43       8.68       14.84       O   ASN 5   18       4.63       8.52       15.30       O   GLY 6   17       4.64       7.62       14.92       A7   ACC   7   6   4.38   0.42   8.51   0.59   14.79   0.44       O   LYS 1   24       0.01       11.45       12.52       O   SER 2   24       0.93       11.05       13.09       O   ASP 3   21       0.38       10.26       13.30       O   ASN 4   21       0.78       10.18       13.08       O   ALA 5   19       1.10       10.42       12.96       A8   ACC   8   5   0.64   0.44   10.67   0.55   12.99   0.29       OE1   GLU 1   116       1.44       −3.73       10.26       OE1   GLN 2   127       1.14       −4.59       10.74       OE1   GLN 6   101       1.56       −2.63       9.89       A29   ACC   29   3   1.38   0.22   −3.65   0.98   10.30   0.42       OG1   THR 2   81       7.15       −6.59       18.23       OG   SER 3   76       7.84       −6.95       17.31       OG   SER 4   76       7.83       −6.93       16.92       OG   SER 5   63       7.26       −6.86       17.98       OG1   THR 6   63       7.53       −6.78       17.57       A45   ACC   45   5   7.52   0.32   −6.82   0.15   17.60   0.52       O   GLU 5   17       3.88       7.64       10.73       A64   ACC   64   1   3.88       7.64       10.73       O   SER 1   94       1.16       −12.13       17.75       O   LYS 2   96       1.98       −11.25       17.47       O   ARG 3   91       2.27       −12.14       16.86       O   LYS 4   91       2.20       −12.05       17.08       O   LYS 5   76       1.29       −12.97       17.19       A22   ACC   22   5   1.78   0.52   −12.11   0.61   17.27   0.35                 Donors                                                     N   ALA 1   11       −9.06       8.04       18.17           N   ALA 2   12       −8.79       8.01       17.55       N   ALA 3   9       −8.95               17.22       N   ALA 4   9       −8.84       8.16       17.46       N   ALA 5   7       −8.61       9.19       17.17       N   ALA 6   6       −8.39       8.86       17.88       D2   DON   2   6   −8.77   0.24   8.45   0.54   17.58   0.39       N   TYR 1   21       −0.42       10.64       9.86       N   ARG 2   21       0.01       10.40       10.61       N   LYS 3   18       0.40       10.07       10.57       N   LYS 4   18       0.32       9.96       10.47       N   MET 5   16       0.86       10.62       10.25       N   LYS 6   15       0.70       10.26       10.69       D5   DON   5   6   0.31   0.46   10.32   0.28   10.41   0.31       N   GLY 1   23       3.65       9.06       10.80       N   ASN 2   23       4.05       8.21       10.77       N   GLY 3   20       4.51       8.63       11.63       N   GLY 4   20       4.53       8.63       11.24       N   ASN 5   18       5.57       8.31       11.98       N   GLY 6   17       4.61       8.02       11.26       D7   DON   7   6   4.49   0.64   8.48   0.37   11.28   0.47       N   LYS 1   24       2.49       10.14       12.86       N   SER 2   24       3.18       9.36       13.12       N   ASP 3   21       3.13       10.15       13.47       N   ASN 4   21       3.34       9.95       13.37       N   ALA 5   19       3.82       9.57       13.45       N   HIS 6   18       3.78       9.34       13.62       D8   DON   8   6   3.29   0.49   9.75   0.37   13.31   0.28       N   MET 1   25       −0.11       11.91       14.72       N   LEU 2   25       1.21       11.60       15.27       N   PHE 3   22       0.10       11.65       14.89       N   LEU 4   22       0.47       11.75       14.68       N   MET 5   20       1.42       12.04       14.55       N   LEU 6   19       1.41       11.53       15.29       D10   DON   10   6   0.75   0.68   11.75   0.20   14.90   0.31       N   GLY 1   55       0.99       −2.06       19.18       N   GLY 2   58       0.23       −1.46       19.18       N   GLY 3   53       0.43       −1.88       18.67       N   GLY 4   53       0.52       −1.82       18.78       N   GLY 5   43       0.23       −1.34       19.06       N   GLY 6   42       0.14       −1.50       19.06       D13   DON   13   6   0.42   0.31   −1.68   0.29   18.99   0.21       N   ARG 1   56       4.28       −2.84       18.05       N   ARG 2   59       3.60       −2.00       18.08       N   LYS 3   54       3.84       −2.10       17.59       N   LYS 4   54       3.92       −2.11       17.43       N   ARG 5   44       3.45       −2.27       17.84       N   ARG 6   43       3.51       −2.24       18.07       D14   DON   14   6   3.77   0.31   −2.26   0.30   17.84   0.28       NE   ARG 1   56       8.78       −3.97       15.50       NZ   LYS 3   54       9.39       −3.41       14.54       NZ   LYS 4   54       9.10       −4.01       14.01       D15   DON   15   3   9.09   0.30   −3.80   0.34   14.68   0.76       N   LYS 1   57       5.58       −0.66       16.65       N   LYS 2   60       4.68       0.38       16.94       N   LYS 3   55       4.80       0.20       16.22       N   LYS 4   55       4.95       0.24       16.06       N   HIS 5   45       4.53       0.07       16.53       N   ARG 6   44       4.80       −0.19       16.60       D18   DON   18   6   4.89   0.37   0.01   0.38   16.50   0.32       NZ   LYS 1   57       6.03       −1.79       11.41       NE2   HIS 5   45       5.83       −0.20       12.35       NE   ARG 6   44       5.42       0.63       11.42       D19   DON   19   3   5.76   0.31   −0.45   1.23   11.73   0.54       N   THR 1   58       4.11       1.68       17.55       N   THR 2   61       3.07       2.49       17.92       N   THR 3   56       2.93       2.04       17.18       N   THR 4   56       3.15       2.15       17.06       N   THR 5   46       2.73       2.26       17.40       N   THR 6   45       3.30       2.25       17.33       D20   DON   20   6   3.21   0.48   2.15   0.27   17.41   0.31       OG   SER 1   78       7.51       −8.07       16.81       N   ASN 2   83       7.95       −9.42       16.07       N   GLU 3   78       8.83       −9.52       15.37       N   GLU 4   78       8.58       −9.52       15.10       N   GLN 5   65       7.90       −9.91       16.99       N   GLN 6   65       8.50       −9.50       16.42       D24   DON   24   6   8.21   0.50   −9.32   0.64   16.12   0.77       N   ARG 1   79       5.13       −9.73       15.64       N   ARG 2   82       5.51       −9.28       16.87       N   ARG 3   77       6.17       −9.41       16.02       N   ARG 4   77       6.01       −9.37       15.82       N   SER 5   64       5.59       −9.07       16.55       N   HIS 6   64       6.00       −8.86       15.99       D25   DON   25   6   5.73   0.39   −9.28   0.30   16.15   0.47       NH1   ARG 1   79       4.49       −8.70       11.66       NH1   ARG 2   82       4.78       −9.07       11.97       D27   DON   27   2   4.63   0.21   −8.88   0.26   11.81   0.22       N   GLY 1   114       −1.20       0.66       16.96       N   GLY 2   125       −2.08       0.99       16.66       N   GLY 3   117       −2.08       0.12       16.11       N   GLY 4   117       −2.00       0.26       16.14       N   GLY 5   96       −1.87       1.30       16.33       N   GLY 6   99       −1.99       1.20       16.31       D35   DON   35   6   −1.87   0.34   0.75   0.49   16.42   0.33       N   GLU 1   116       −2.20       −0.54       11.97       N   GLN 2   127       −2.51       −1.22       12.03       N   SER 3   119       −3.51       −2.29       11.74       N   ALA 4   119       −3.63       −2.67       11.96       N   ARG 5   98       −2.81       −0.91       11.18       N   GLN 6   101       −2.81       −1.25       12.00       D37   DON   37   6   −2.91   0.56   −1.48   0.83   11.81   0.33       N   ILE 1   117       −2.58       −2.52       13.89       N   LEU 2   128       −3.06       −2.83       14.28       N   VAL 3   120       −3.71       −3.84       14.05       N   VAL 4   120       −3.83       −3.92       14.47       N   VAL 5   99       −3.54       −2.56       13.37       N   ILE 6   102       −3.10       −2.76       14.27       D38   DON   38   6   −3.30   0.47   −3.07   0.64   14.06   0.39       OH   TYR 1   118       −5.90       3.87       18.74       OH   TYR 2   129       −6.34       4.00       17.96       OH   TYR 3   121       −6.27       3.45       17.00       OH   TYR 4   121       −6.58       3.42       17.85       OH   TYR 5   100       −6.50       4.59       17.32       D40   DON   40   5   −6.32   0.26   3.86   0.48   17.78   0.67       OG1   THR 2   81       7.15       −6.59       18.23       OG   SER 3   76       7.84       −6.95       17.31       OG   SER 4   76       7.83       −6.93       16.92       OG   SER 5   63       7.26       −6.86       17.98       OG1   THR 6   63       7.53       −6.78       17.57       D53   DON   53   5   7.52   0.32   −6.82   0.15   17.60   0.52       NZ   LYS 3   55       4.59       5.07       10.49       NZ   LYS 4   55       4.60       4.32       11.03       D58   DON   58   2   4.59   0.01   4.70   0.53   10.76   0.38                 Waters                                                     O   HOH 1   360       3.79       4.24       10.23           O   HOH 4   814       2.42       4.72       9.84       O   HOH 6   302       3.16       4.08       10.62       W5   WAT   5   3   3.12   0.69   4.35   0.33   10.23   0.39       O   HOH 3   194       2.39       6.87       10.29       O   HOH 4   220       2.39       7.13       10.16       O   HOH 6   208       2.21       6.90       10.19       W7   WAT   7   3   2.33   0.11   6.97   0.14   10.21   0.07       O   HOH 3   238       2.04       3.26       9.48       O   HOH 6   301       0.72       3.27       8.67       W9   WAT   9   2   1.38   0.94   3.27   0.01   9.07   0.57       O   HOH 3   255       −2.28       −11.29       15.13       O   HOH 4   493       −2.82       −10.95       15.67       O   HOH 6   266       −2.62       −12.63       15.07       W10   WAT   10   3   −2.58   0.27   −11.63   0.89   15.29   0.33                    
     [0210]               TABLE 9A                          Pharmacofamily 7 Subset                                         rmsd                   from                   Family       Molecule #   pdb   type   Avg.                                     1   1GET   Glutathione Reductase ( E. coli )   0.34       2   1GRB   Glutathione Reductase (human)   0.66       3   2NPX   NADH Peroxidase (strep faecalis)   0.82       4   1TDF   Thioredoxin Reductase ( E. Coil )   0.89       5   1TYP   Trypanothione Reductase   2.17*               ( Crithidia fasciculata )                            
     [0211]               TABLE 9B                          Polypeptide and Solvent Interactors (average coordinates)                                                     residue-                                   atom name   mol. #   total   x   σx   y   σy   z   σz                         Acceptors                                                 A11   ACC   4   −3.74   0.43   4.39   1.20   14.96   0.59       A12   ACC   2   −4.46   0.14   6.91   0.01   13.10   0.51       A21   ACC   3   −7.67   0.40   −0.28   0.63   6.97   0.49       A27   ACC   5   −6.51   0.79   8.70   0.33   10.16   0.42       A37   ACC   1   9.32   —   1.02   —   6.96   —       A38   ACC   1   8.04   —   2.39   —   7.96   —       A43 (D46)   ACC   1   −1.72   —   2.70   —   6.02   —                 Donors                                                 D8   DON   5   0.53   0.17   4.12   0.23   9.87   0.65       D10   DON   4   −0.29   0.12   2.72   0.33   12.17   0.28       D13   DON   4   11.13   0.14   −1.28   0.24   5.56   0.39       D14   DON   4   10.96   0.24   −3.44   0.24   4.80   0.45       D15   DON   4   9.51   0.04   −1.85   0.43   4.07   0.31       D18   DON   3   8.97   1.77   3.01   1.32   1.85   0.48       D23   DON   5   2.38   0.54   −3.84   0.13   9.65   0.30       D46 (A43)   DON   1   −1.72   —   2.70   —   6.02   —       D58   DON   1   3.70   —   2.30   —   3.85   —       D62   DON   1   −5.70       2.24   —   2.88   —                 Waters                                                 W2   WAT   3   0.36   0.44   −3.68   0.38   12.46   0.18       W4   WAT   4   2.93   0.16   1.13   0.26   10.91   0.18       W6   WAT   5   −9.38   0.47   6.86   0.35   8.83   0.85       W10   WAT   2   0.45   0.22   3.40   0.19   5.75   0.60       W13   WAT   3   −6.28   0.08   −3.16   0.26   9.68   0.49                    
     [0212]               TABLE 9C                          NAD(P) Conformer Model                                             atom name   total   x   σx   y   σy   z   σz                                                     PA   5   0.93   0.13   −0.09   0.32   6.93   0.27       O1A   5   0.14   0.09   1.08   0.42   6.77   0.65       O2A   5   1.08   0.29   −1.04   0.52   5.87   0.08       O5&#39;A   5   2.38   0.11   0.41   0.17   7.37   0.16       C5&#39;A   5   3.43   0.24   −0.49   0.18   7.71   0.15       C4&#39;A   5   4.73   0.18   0.09   0.26   7.34   0.36       O4&#39;A   5   5.80   0.27   −0.54   0.45   7.99   0.17       C3&#39;A   5   5.07   0.14   −0.04   0.62   5.96   0.38       O3&#39;A   5   4.90   0.67   0.84   0.92   5.36   0.96       C2&#39;A   5   6.35   0.42   −0.33   0.34   5.72   0.24       O2&#39;A   5   6.88   0.18   0.71   0.74   5.16   0.35       C1&#39;A   5   6.90   0.27   −0.63   0.31   7.08   0.22       N9A   5   7.56   0.16   −1.93   0.24   7.16   0.17       C8A   5   7.19   0.18   −3.11   0.27   6.55   0.20       N7A   5   7.98   0.18   −4.12   0.22   6.87   0.22       C5A   5   8.90   0.17   −3.57   0.15   7.72   0.19       C6A   5   10.00   0.19   −4.16   0.07   8.39   0.21       N6A   5   10.34   0.27   −5.42   0.05   8.23   0.27       N1A   5   10.72   0.16   −3.34   0.07   9.17   0.23       C2A   5   10.42   0.10   −2.04   0.11   9.27   0.21       N3A   5   9.45   0.10   −1.39   0.13   8.66   0.19       C4A   5   8.68   0.13   −2.21   0.16   7.90   0.17       O3   5   0.38   0.10   −0.91   0.20   8.17   0.20       PN   5   −0.15   0.14   −0.48   0.48   9.57   0.41       O2N   5   0.14   0.49   0.83   0.44   9.75   0.95       O1N   5   0.30   0.16   −1.45   1.05   10.42   0.24       O5&#39;N   5   −1.69   0.09   −0.59   0.27   9.56   0.17       C5&#39;N   5   −2.47   0.06   −1.57   0.23   8.85   0.37       C4&#39;N   5   −3.70   0.14   −0.94   0.26   8.22   0.15       O4&#39;N   5   −4.71   0.05   −0.62   0.08   9.19   0.03       C3&#39;N   5   −3.46   0.22   0.35   0.46   7.53   0.17       O3&#39;N   5   −3.17   0.71   0.29   0.62   6.28   0.17       C2&#39;N   5   −4.65   0.52   1.11   0.18   7.65   0.18       O2&#39;N   5   −5.28   0.75   0.98   0.55   6.52   0.28       C1&#39;N   5   −5.38   0.18   0.60   0.07   8.82   0.16       N1N   5   −5.34   0.08   1.60   0.06   9.91   0.18       C2N   5   −5.97   0.21   2.80   0.05   9.75   0.25       C3N   5   −5.93   0.17   3.83   0.08   10.68   0.26       C7N   5   −6.64   0.26   5.15   0.08   10.42   0.36       O7N   5   −7.25   0.57   5.32   0.37   9.88   1.12       N7N   5   −6.58   0.34   6.07   0.28   10.81   0.74       C4N   5   −5.15   0.02   3.67   0.21   11.82   0.22       C5N   5   −4.45   0.21   2.46   0.27   11.97   0.23       C6N   5   −4.58   0.19   1.45   0.20   11.02   0.20       P2&#39;   3   8.26   0.32   1.61   0.37   4.55   0.21       OP1   3   8.14   0.53   1.73   0.94   3.60   0.75       OP2   3   9.03   0.56   1.00   0.50   4.62   1.13       OP3   3   8.62   0.79   2.41   1.40   4.94   0.68                    
     [0213]               TABLE 9D                          Polypeptide and Solvent Interactors                                                     atom   residue-   residue   to-                               name   mol. #   #   tal   x   σx   y   σy   z   σz                         Acceptors                                                     OE1   GLU 1   181       −3.88       5.25       14.75           OE1   GLU 2   201       −4.15       5.48       14.38       OE1   GLU 3   163       −3.79       3.89       15.77       OE1   GLU 4   159       −3.14       2.93       14.95       A11   ACC   11   4   −3.74   0.43   4.39   1.20   14.96   0.59       OE2   GLU 1   181       −4.37       6.90       13.45       OE2   GLU 2   201       −4.56       6.92       12.74       A12   ACC   12   2   −4.46   0.14   6.91   0.01   13.10   0.51       O   GLU 1   309       −8.06       0.25       7.52       O   LEU 2   337       −7.71       −0.11       6.85       O   ALA 3   297       −7.26       −0.97       6.55       A21   ACC   21   3   −7.67   0.40   −0.28   0.63   6.97   0.49       OE2   GLU 1   309       −4.36       −3.87       5.45       A23   ACC   23   1   −4.36       −3.87       5.45       O   VAL 1   342       −7.20       8.83       10.41       O   VAL 2   370       −6.94       8.48       9.46       O   GLY 3   328       −6.79       9.23       10.09       OE2   GLU 4   183       −5.19       8.47       10.50       O   ALA 5   365       −6.46       8.51       10.35       A27   ACC   27   5   −6.51   0.79   8.70   0.33   10.16   0.42       OD1   ASP 3   179       9.32       1.02       6.96       A37   ACC   37   1   9.32       1.02       6.96       OD2   ASP 3   179       8.04       2.39       7.96       A38   ACC   38   1   8.04       2.39       7.96       OH   TYR 3   188       −1.72       2.70       6.02       A43   ACC   43   1   −1.72       2.70       6.02                 Donors                                                     N   TYR 1   177       0.42       4.12       9.29           N   TYR 2   197       0.54       3.95       9.16       N   TYR 3   159       0.39       3.86       9.94       N   ASN 4   155       0.81       4.22       10.27       N   TYR 5   198       0.50       4.45       10.69       D8   DON   8   5   0.53   0.17   4.12   0.23   9.87   0.65       N   ILE 1   178       −0.30       3.00       11.99       N   ILE 2   198       −0.19       3.01       11.87       N   ILE 3   160       −0.46       2.46       12.45       N   THR 4   156       −0.21       2.41       12.37       D10   DON   10   4   −0.29   0.12   2.72   0.33   12.17   0.28       NE   ARG 1   198       10.97       −1.63       5.67       NE   ARG 2   218       11.27       −1.15       5.31       NE   ARG 4   176       11.22       −1.28       5.21       NE   ARG 5   222       11.04       −1.09       6.07       D13   DON   13   4   11.13   0.14   −1.28   0.24   5.56   0.39       NH1   ARG 1   198       11.24       −3.80       4.93       NH1   ARG 2   218       10.89       −3.37       4.77       NH1   ARG 4   176       10.67       −3.32       4.21       NH1   ARG 5   222       11.05       −3.27       5.30       D14   DON   14   4   10.96   0.24   −3.44   0.24   4.80   0.45       NH2   ARG 1   198       9.54       −2.45       4.11       VAL   ARG 2   218       9.46       −1.77       4.00       1       NH2   ARG 4   176       9.50       −1.43       3.70       NH2   ARG 5   222       9.55       −1.74       4.46       D15   DON   15   4   9.51   0.04   −1.85   0.43   4.07   0.31       NE   ARG 4   177       10.99       4.32       2.39       NH1   ARG 1   204       8.17       3.03       1.71       NH1   ARG 5   228       7.75       1.68       1.45       D18   DON   18   3   8.97   1.77   3.01   1.32   1.85   0.48       N   GLY 1   262       2.72       −3.76       9.55       N   GLY 2   290       2.62       −3.74       9.51       N   GLY 3   243       2.38       −4.07       9.32       N   GLY 4   244       1.45       −3.80       10.09       N   GLY 5   286       2.74       −3.85       9.80       D23   DON   23   5   2.38   0.54   −3.84   0.13   9.65   0.30       OH   TYR 3   188       −1.72       2.70       6.02       D46   DON   46   1   −1.72       2.70       6.02       NH1   ARG 4   181       3.70       2.30       3.85       D58   DON   58   1   3.70       2.30       3.85       ND2   ASN 4   260       −5.70       2.24       2.88       D62   DON   62   1   −5.70       2.24       2.88                 Waters                                                     O   HOH 1   35       0.68       −3.50       12.51           O   HOH 2   511       0.54       −3.42       12.61       O   HOH 3   461       −0.15       −4.12       12.26       W2   WAT   2   3   0.36   0.44   −3.68   0.38   12.46   0.18       O   HOH 1   70       2.74       1.12       10.80       O   HOH 2   524       3.09       1.48       10.72       O   HOH 3   901       2.86       1.06       11.09       O   HOH 4   618       3.03       0.85       11.05       W4   WAT   4   4   2.93   0.16   1.13   0.26   10.91   0.18       O   HOH 1   115       −9.62       7.01       9.04       O   HOH 2   514       −9.26       6.65       7.93       O   HOH 3   499       −8.71       7.08       8.17       O   HOH 4   861       −9.99       6.36       10.10       O   HOH 5   121       −9.33       7.20       8.93       W6   WAT   6   5   −9.38   0.47   6.86   0.35   8.83   0.85       O   HOH 1   171       0.30       3.54       6.18       O   HOH 2   984       0.61       3.27       5.33       W10   WAT   10   2   0.45   0.22   3.40   0.19   5.75   0.60       O   HOH 1   250       −6.35       −3.18       10.09       O   HOH 2   500       −6.31       −2.89       9.82       O   HOH 3   467       −6.19       −3.41       9.14       W13   WAT   13   3   −6.28   0.08   −3.16   0.26   9.68   0.49                    
     [0214]               TABLE 10A                          Pharmacofamily 8 Subset                                         rmsd                   from                   family       Molecule #   pdb   type   avg.               1   1QGA   Ferrodoxin Reductase (pea)   0.61       2   P450′   P450 reductase (rat)   0.35                    
     [0215]               TABLE 10B                          Polypeptide and Solvent Interactors (average coordinates)                                                 atom   residue-                                   name   mol. #   total   x   σx   y   σy   z   σz                         Acceptors                                                 A2   ACC   2   0.63   0.38   −6.60   0.21   −7.09   0.16       A8   ACC   2   −2.87   0.25   −3.55   0.64   −0.51   0.02       A11   ACC   2   −4.28   0.30   8.10   0.34   3.52   0.33       A14   ACC   2   −7.58   0.10   8.62   0.24   3.69   0.19       A18   ACC   2   −12.53   0.11   8.89   0.59   0.72   0.62       A21   ACC   2   −8.28   0.08   9.45   0.25   −6.25   0.84       A23   ACC   2   −1.15   0.00   −2.54   0.21   −7.56   0.09       A29   ACC   2   −1.63   0.84   −6.66   0.42   −10.70   0.06       A31   ACC   2   −7.49   0.70   −5.59   0.66   −9.88   0.66       A32   ACC   1   −8.95   —   −3.74   —   −4.78   —                 Donors                                                 D2   DON   2   0.63   0.38   −6.60   0.21   −7.09   0.16       D4   DON   2   −6.69   0.23   −1.87   0.78   5.73   0.27       D8   DON   2   −1.98   0.25   −0.80   0.53   −0.07   0.05       D9   DON   2   −2.87   0.25   −3.55   0.64   −0.51   0.02       D15   DON   2   −7.58   0.10   8.62   0.24   3.69   0.19       D18   DON   2   −10.73   0.10   5.15   0.70   6.85   0.21       D21   DON   2   −12.39   0.55   8.95   0.83   4.42   0.46       D23   DON   2   −12.53   0.11   8.89   0.59   0.72   0.62       D26   DON   2   −10.08   0.70   9.97   0.39   −5.61   0.35                    
     [0216]               TABLE 10C                          NAD (P) Conformer Model                                             atom name   number   x   σx   y   σy   z   σz                                                     PA   2   −6.90   0.19   1.29   0.01   2.19   0.44       O1A   2   −8.23   0.13   0.84   0.28   2.29   1.01       O2A   2   −6.22   0.68   1.25   0.00   3.45   0.19       O5&#39;A   2   −6.94   0.05   2.74   0.01   1.67   0.46       C5&#39;A   2   −5.96   0.32   3.31   0.21   0.99   0.16       C4&#39;A   2   −6.21   0.28   4.77   0.19   0.81   0.08       O4&#39;A   2   −7.07   0.21   4.93   0.07   −0.33   0.12       C3&#39;A   2   −6.95   0.32   5.45   0.19   1.99   0.09       O3&#39;A   2   −6.38   0.22   6.74   0.20   2.25   0.09       C2&#39;A   2   −8.36   0.28   5.60   0.08   1.51   0.12       O2&#39;A   2   −9.02   0.09   6.71   0.01   2.15   0.10       C1&#39;A   2   −8.10   0.23   5.82   0.11   0.05   0.07       N9A   2   −9.26   0.18   5.67   0.07   −0.81   0.09       C8A   2   −10.48   0.15   5.08   0.02   −0.58   0.05       N7A   2   −11.35   0.01   5.15   0.09   −1.61   0.14       C5A   2   −10.62   0.05   5.84   0.01   −2.55   0.11       C6A   2   −10.98   0.07   6.27   0.00   −3.84   0.10       N6A   2   −12.17   0.06   6.02   0.00   −4.36   0.08       N1A   2   −10.08   0.13   6.95   0.04   −4.59   0.09       C2A   2   −8.88   0.12   7.22   0.07   −4.10   0.04       N3A   2   −8.46   0.02   6.87   0.15   −2.90   0.02       C4A   2   −9.35   0.07   6.17   0.04   −2.06   0.07       O3   2   −6.11   0.32   0.30   0.20   1.21   0.13       PN   2   −5.73   0.14   −1.29   0.24   1.48   0.01       O1N   2   −6.50   0.06   −1.63   0.42   2.69   0.13       O2N   2   −4.30   0.14   −1.48   0.06   1.62   0.06       O5&#39;N   2   −6.26   0.37   −2.13   0.26   0.26   0.06       C5&#39;N   2   −5.67   0.29   −2.09   0.15   −1.01   0.07       C4&#39;N   2   −6.63   0.26   −2.81   0.33   −1.93   0.11       O4&#39;N   2   −6.11   0.28   −2.90   0.27   −3.27   0.09       C3&#39;N   2   −6.95   0.06   −4.24   0.38   −1.45   0.14       O3&#39;N   2   −8.35   0.03   −4.47   0.60   −1.50   0.32       C2&#39;N   2   −6.22   0.01   −5.16   0.30   −2.41   0.06       O2&#39;N   2   −7.01   0.15   −6.29   0.42   −2.74   0.07       C1&#39;N   2   −5.90   0.11   −4.29   0.22   −3.62   0.04       NN1   2   −4.55   0.05   −4.52   0.01   −4.21   0.01       C2N   2   −4.50   0.03   −5.07   0.06   −5.47   0.05       C3N   2   −3.29   0.08   −5.32   0.10   −6.13   0.01       C7N   2   −3.24   0.24   −5.90   0.02   −7.52   0.03       O7N   2   −3.24   1.75   −6.01   0.02   −8.11   0.03       NN7   2   −3.18   1.32   −6.31   0.10   −8.11   0.04       C4N   2   −2.09   0.01   −5.00   0.39   −5.44   0.02       C5N   2   −2.15   0.06   −4.44   0.46   −4.14   0.07       C6N   2   −3.40   0.11   −4.21   0.25   −3.54   0.08       P2&#39;   2   −10.21   0.02   6.47   0.10   3.22   0.06       OP1   2   −10.72   1.21   5.88   0.71   3.20   1.26       OP2   2   −10.31   0.01   7.62   0.12   4.24   0.11       OP3   2   −10.73   1.02   5.69   1.01   3.24   0.93                    
     [0217]               TABLE 10D                          Polypeptide and Solvent Interactors                                                         residue-                                       atom name   mol. #   residue #   total   x   σx   y   σy   z   σz                         Acceptors                                                     OG   SER 1   90       0.366       −6.74       −6.97           OG   SER 2   457       0.899       −6.45       −7.20       A2   ACC   2   2   0.633   0.38   −6.60   0.21   −7.09   0.16       OG1   THR 1   166       −2.694       −4.00       −0.53       OG1   THR 2   535       −3.041       −3.09       −0.50       A8   ACC   8   2   −2.867   0.25   −3.55   0.64   −0.51   0.02       O   VAL 1   198       −4.071       7.86       3.28       O   CYS 2   566       −4.494       8.34       3.75       A11   ACC   11   2   −4.282   0.30   8.10   0.34   3.52   0.33       OG   SER 1   228       −7.649       8.79       3.55       OG   SER 2   596       −7.509       8.45       3.83       A14   ACC   14   2   −7.579   0.10   8.62   0.24   3.69   0.19       OH   TYR 1   240       −12.45       9.30       1.16       OH   TYR 2   604       −12.61       8.47       0.29       A18   ACC   18   2   −12.53   0.11   8.89   0.59   0.72   0.62       OE1   GLN 1   242       −8.226       9.28       −6.85       OE1   GLN 2   606       −8.34       9.63       −5.65       A21   ACC   21   2   −8.283   0.08   9.45   0.25   −6.25   0.84       SG   CYS 1   266       −1.15       −2.68       −7.63       SG   CYS 2   630       −1.148       −2.39       −7.50       A23   ACC   23   2   −1.149   0.00   −2.54   0.21   −7.56   0.09       OE1   GLU 1   306       −1.033       −6.96       −10.66       OD1   ASP 2   675       −2.227       −6.36       −10.74       A29   ACC   29   2   −1.63   0.84   −6.66   0.42   −10.70   0.06       O   VAL 1   307       −7.979       −5.12       −9.41       O   VAL 2   676       −6.991       −6.05       −10.34       A31   ACC   31   2   −7.485   0.70   −5.59   0.66   −9.88   0.66       O   TRP 1   308       −8.949       −3.74       −4.78       A32   ACC   32   1   −8.949       −3.74       −4.78                 Donors                                                     OG   SER 1   90       0.366       −6.74       −6.97           OG   SER 2   457       0.899       −6.45       −7.20       D2   DON   2   2   0.633   0.38   −6.60   0.21   −7.09   0.16       NZ   LYS 1   110       −6.847       −2.42       5.92       NH1   ARG 2   298       −6.526       −1.32       5.54       D4   DON   4   2   −6.687   0.23   −1.87   0.78   5.73   0.27       N   THR 1   166       −1.805       −1.18       −0.10       N   THR 2   535       −2.152       −0.42       −0.03       D8   DON   8   2   −1.978   0.25   −0.80   0.53   −0.07   0.05       OG1   THR 1   166       −2.694       −4.00       −0.53       OG1   THR 2   535       −3.041       −3.09       −0.50       D9   DON   9   2   −2.867   0.25   −3.55   0.64   −0.51   0.02       OG   SER 1   228       −7.649       8.79       3.55       OG   SER 2   596       −7.509       8.45       3.83       D15   DON   15   2   −7.579   0.10   8.62   0.24   3.69   0.19       NH1   ARG 1   229       −10.66       5.64       7.00       NH2   ARG 2   597       −10.81       4.65       6.71       D18   DON   18   2   −10.73   0.10   5.15   0.70   6.85   0.21       NZ   LYS 1   238       −12       9.53       4.09       NZ   LYS 2   602       −12.78       8.36       4.75       D21   DON   21   2   −12.39   0.55   8.95   0.83   4.42   0.46       OH   TYR 1   240       −12.45       9.30       1.16       OH   TYR 2   604       −12.61       8.47       0.29       D23   DON   23   2   −12.53   0.11   8.89   0.59   0.72   0.62       NE2   GLN 1   242       −9.587       10.24       −5.36       NE2   GLN 2   606       −10.58       9.70       −5.85       D26   DON   26   2   −10.08   0.70   9.97   0.39   −5.61   0.35                    
     [0218] Coordinates for the conformer and pharmacophore models and data used in their construction is presented in Tables 3-10 above. Part A of each Table lists subset of structures used in constructing the model including molecule numbers for cross-referencing between parts A-C, the PDB accession number, the name of the polypeptide, and the RMSD from the pharmacocluster average. Part B of each Table lists the average coordinates for heteroatoms and waters of the pharmacophore model and includes the atom name (cross referenced to part D), designation of interaction (“ACC,” acceptor; “DON,” donor; and “WAT,” water), total number of atoms included in the calculation of the average, and X, Y, Z coordinates with respective standard deviations (σ). Part C of each Table lists the coordinates of the conformer model using the atom designations of FIG. 2 and X, Y, Z coordinates with respective standard deviations (σ). Part D of each Table lists the coordinates for interacting molecules used to determine the pharmacophore model including the atom name, residue molecule # (which identifies the residue type and molecule number cross-referenced to Part A), residue number from the PDB structure, total number of atoms summed for the average coordinates, and X, Y, Z coordinates with respective standard deviations (σ). The bolded entries in part D correspond to the average values reported in part B. Atom names are identified according to IUPAC recommendations as described for example in Markley et al.,  Pure and Appl. Chem.  70:117-142 (1998).  
     [0219] Throughout this application various publications have been referenced. The disclosures of these publications in their entireties are hereby incorporated by reference in this application in order to more fully describe the state of the art to which this invention pertains.  
     [0220] Although the invention has been described with reference to the disclosed embodiments, those skilled in the art will readily appreciate that the specific details are only illustrative of the invention. It is understood that modifications which do not substantially affect the activity of the various embodiments of this invention are also included within the definition of the invention provided herein. Therefore, it should be understood that various modifications can be made without departing from the spirit of the invention. Accordingly, the invention is limited only by the following claims.