bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Quantitative Stereo‐Structure Activity Relationship Analysis of the Binding of Promiscuous Chiral Ligands to Different Receptors
Authors: Lehmann Pedro A. F. 
Published: October 2006

AbstractMany important compounds of pharmacological interest bind with high affinities to more than one receptor (promiscuous ligands). If in addition they are chiral, the stereoselectivity each receptor displays towards pairs of such stereoisomeric ligands is of theoretical and practical importance.The recent literature was culled for data sets in which affinity values were provided for both isomers of a stereoisomeric ligand at three or more receptors or receptor subtypes. Their multiple eudismic‐affinity analysis showed that in general stereoisomeric potency ratios increase as a function of affinity, thus validating an extension of Pfeiffer's Rule.The increase in stereoselectivity per unit increase in eutomer affinity (M.E.A.Q) tends towards 0.5 with most values lying between 0.3 and 0.7. A simple explanation is offered for this at the molecular level in which the M.E.A.Q. of 0.5 is interpreted in terms of the transfer of a methylene group from a lipidic to an aqueous environment.The implications for rational drug design and receptor speciation of this generalization are analyzed and it is suggested that quantitative stereo‐structure activity relationships (QSSAR) must be made an integral part of QSAR.
Determination of Octanol/Water Partition Coefficients of Certain Organophosphorus Compounds Using High‐Performance Liquid Chromatography
Authors: Krikorian S. Edward , Chorn Trevor A. , King James W. 
Published: October 2006

AbstractOctanol/water partition coefficients (log P) for a series of dialkyl alkylphosphonates, dialkyl alkylphosphonothionates, and an alkyl alkylphosphinate have been estimated using reversed‐phase high‐performance liquid chromatography. The test compounds proved to be readily amenable to the chromatographic procedures employed, although the more lipophilic compounds appeared to be more tolerant to variations in the chromatographic conditions and methods of data handling than were the less lipophilic compounds with regard to the precision and accuracy of the log P values obtained from the retention data. The methodology was validated by carrying out shake‐flask experiments with two of the test samples. The rank order of log P values obtained was reasonably predictable, based on the sizes of the alkyl substituents present. The enhancement of lipophilic character attributable to replacement of oxygen by sulfur in the PO group is also evident from the results. The data for the phosphonates permit the calculation of a value for the hydrophobic fragmental constant for the OPO2 group (f = −2.79).
Design of a New Substituted 2,4‐Diamino‐5‐benzylpyrimidine as Inhibitor of Bacterial Dihydrofolate Reductase Assisted by Molecular Graphics
Authors: Czaplinsky Karl‐H. , Kansy Manfred , Seydel Joachim K. , Haller Rolf 
Published: October 2006

AbstractA new highly active inhibitor of bacterial DHFR has been developed supported by computer graphics. The new benzylpyrimidine is especially active against mycobacteria due to its favourable properties with respect to cell wall permeation.
A Pharmacophore Hypothesis for Antidepressant Activity
Authors: Andrews Peter R. , Craik David J. , Munro Sharon L. 
Published: October 2006

AbstractPrevious studies of conformation‐activity relationships of antidepressant drugs are extended by considering not only more antidepressant structures, but also modelling the positions of key receptor groups. This is achieved using the program HAYSTACK to search all possible conformations of both the highly flexible tricyclic antidepressants such as imipramine and amitriptyline, and more conformationally constrained atypical antidepressants such as nomifensine and mianserin. For each compound the set of possible conformations is filtered using both energetic and distance‐geometry criteria until finally those conformations which combine lowest energy with best fit to a general receptor model are obtained. It is shown that all 12 tricyclic and atypical antidepressants considered may act at a single receptor.
Conformational Analysis of Flexible Antidepressant Drugs
Authors: Munro Sharon L. , Craik David J. , Andrews Peter R. 
Published: October 2006

AbstractA complete conformational analysis is reported for the two highly flexible antidepressant drugs imipramine and amitriptyline. In both cases, all sidechain torsion angles and conformational variables associated with the tricyclic ring systems were varied in a step‐wise manner using simple molecular mechanics calculations. The results of these studies provided an overview of the mobility of both molecules. The molecular mechanics data also provided the basis for more detailed molecular orbital calculations which were used to optimize specific low‐energy conformations and conformational transitions. The results are presented using a variety of graphical techniques, including a five‐dimensional SUPERMAP which simultaneously depicts four conformational variables and the molecular energy. Both imipramine and amitriptyline are shown to be extremely flexible molecules, with the calculated barriers to conformational transitions being generally consistent with those observed using NMR spectroscopy.
An Extended QSAR Analysis of Some 4‐Aminodiphenylsulfone Antibacterial Agents Using Molecular Modeling and LFE‐Relationships
Authors: Hopfinger A. J. , De Compadre Rosa L. Lopez , Koehler M. G. , Emery S. , Seydel J. K. 
Published: October 2006

AbstractThe QSAR between free‐space, intramolecular conformational entropy, S, and inhibition potency, pC, of dihydropteroate synthase from dapsone sensitive M. lufu bacterial strains [1] was extended from 36 to 53 substituted 4‐aminodiphenylsulfones. In addition, S was used to establish QSARs for dihydropteroate synthase pC values from dapsone resistant M. lufu and both sensitive and resistant M. smegmatis bacterial strains. The resulting QSARs suggest there are no discernible specificity factors among the dihydropteroate synthases from the four strains. Environmental effects on S were evaluated by computing and comparing intramolecular conformational entropies in both free‐space and an aqueous medium. Overall, the aqueous solvation effects increase the intramolecular entropies by making substituents more flexible. However, a very significant correlation persists between the solvent‐dependent S and pC even though the QSAR is not as meaningful as that found for free‐space S.
Quantitative Structure‐Activity Relationships in a Set of Local Anesthetic Agents
Authors: Recanatini Maurizio , Valenti Piero , Re Paolo Da 
Published: October 2006

AbstractA QSAR analysis has been carried out on a set of local anesthetic drugs structurally related to lidocaine. The surface and the infiltration activities and the acute toxicity have been examined, and their dependence upon structural as well as physico‐chemical parameters has been expressed in terms of both linear and non‐linear models. The results embodied in the correlation equations are discussed at the light of recent theories on the local anesthetic action. In accord with these theories, the hydro‐/lipophilic balance of the molecules has a basic role in modulating the potency of the compounds, also if this property can be “hidden” behind some structural features. Once the contributions of these structural characteristics have been ruled out (by means of indicator variables), the dependence of the biological response on the distribution coefficient can be quantitatively assessed.
Quantitative Structure‐Activity Relationships in Insecticidal Pyrethroid Ethers
Authors: Winkler David A. , Holan George , Johnson Wynona M. P. , Virgona Chris T. F. , Jarvis Karen E. 
Published: October 2006

AbstractA series of twenty‐six insecticidal pyrethroid ethers were subjected to multiple regression QSAR analysis. The results indicated that candidate insecticides should have a lipophilicity, as expressed in the log of the calculated octanol/water partition coefficient, of approximately 5.5. There was a general, negative correlation of activity with molar refractivity, suggesting that molecular size, or volume, and polarizability should not be too large for optimum insecticidal activity.The substituents on the aromatic ring adjacent to the cyclopropyl moiety appear to exert their primary influence via electronic effects. For optimum activity strongly electron donating para substituents are required. Electron‐withdrawing or donating effects, size and lipophilicity of the substituents on the cyclopropyl ring appear to influence the insecticidal activity. Substituents which are small, not very polarizable, not very lipid soluble and which have a positive polar electronic substituent constant are likely to be the most effective. This is consistent with the hypothesis of the pyrethroids and other toxins acting at specific receptors adjacent to ion channels embedded in nerve membranes, causing partial blockade of these sodium, or other ion, channels.There were very few changes made to the substituents on the other aromatic ring. The results indicated that electron withdrawing groups were favoured as substituents on that ring.
Structure‐Activity Relationships for Unsaturated Dialdehydes 2. A PLS Correlation of Theoretical Descriptors for Six Compounds with Mutagenic Activity in the Ames Salmonella Assay
Authors: Nilsson Lena M. , Carter Robert E. , Sterner Olov , Liljefors Tommy 
Published: October 2006

AbstractA QSAR model has been developed for the quantitative prediction of mutagenic activity in a class of unsaturated dialdehydes. The conformers of each dialdehyde were obtained from molecular mechanics (MM) calculations. The MM results were used to extract descriptors to represent the three‐dimensional structure of each compound. Thirty‐one theoretical descriptors (e.g. from MM and CNDO calculations) were correlated with the mutagenic activities of six unsaturated dialdehydes in three strains in the Ames Salmonella assay. The method of partial least squares in latent variables, PLS, was chosen for the multivariate statistical analysis. The activity of a seventh dialdehyde was predicted from this model, in encouragingly good agreement with experiment. The set of compounds is admittedly a small one, but as an initial investigation the results show the potential of this approach to QSAR modeling.
Multivariate Parametrization of 55 Coded and Non‐Coded Amino Acids
Authors: Jonsson Jörgen , Eriksson Lennart , Hellberg Sven , Sjöström Michael , Wold Svante 
Published: October 2006

AbstractThe previously derived z‐scales for the 20 coded amino acids have been extended to cover non‐coded amino acids. In total, 55 amino acids (35 non‐coded) were multivariately characterized by seven TLC variables, three NMR variables and two theoretical variables, resulting in three extended z‐scales (z1′, z2′ and z3′). These scales were validated in QSAR studies on two different series of peptides. They were used to model 40 bradykinin potentiating pentapeptides, and 48 dipeptides with bitter taste. The former series contained 10 peptides with non‐coded amino acids. Thus, the extended z‐scales were validated both for their coded and non‐coded parts.
High Performance Liquid Chromatographic Methods and Procedures of Hydrophobicity Determination
Authors: Kaliszan Roman 
Published: October 2006

AbstractNew methods and procedures of hydrophobicity determination employing high performance liquid chromatography are reviewed. After a brief analysis of the state of the art regarding the earlier developed methods, the approaches reported since 1986 are described. Advantages and limitations are discussed of the following HPLC stationary phase materials: poly (styrene‐divinylbenzene) copolymers, alkyl‐derivatized polymers, polymers immobilized on alumina and silanol‐deactivated silica‐based reversed‐phase materials. Separate paragraph is devoted to centrifugal partition chromatography (CPC) as a method of hydrophobicity determination. The new methods and materials reduce (at least partially) the limitations of alkyl‐bonded silica phases, i.e., instability at pH above 8 and specific activity of free silanol groups of the support. At the same time the new HPLC systems are of a wider hydrophobicity measuring range and are more easy to handle than the 1‐octanol‐like systems. Several of the methods proposed seem to be convenient, reliable and to yield hydrophobicity data otherwise not readily available. Providing that appropriate columns are commercially distributed the new methods may replace soon the established HPLC procedures in an average QSAR laboratory.
Correlation Analysis and Molecular Modeling of Cholecystokinin Inhibitors
Authors: Coats Eugene A. , Knittel James J. 
Published: October 2006

AbstractQuantitative structure‐activity relationships for a series of N‐(R‐benzoyl)‐glutamic acid α‐alkylamides as cholecystokinin inhibitors have been elucidated. The relationships clearly define a hydrophobic binding pocket on the receptor which accomodates the alkylamides. A second hydrophobic binding region appears to interact with the benzoyl substituents. Computer graphic modeling suggests that these hydrophobic binding regions correspond to Met31 and Trp30 amino acid residues of the peptide agonist. A comparative analysis of potential carboxylate binding via GRID provides a quantitative assessment of similarities and differences between the glutamate inhibitors and the peptide agonist.
Comparison of Chemometric Models for QSAR
Authors: Cruciani Gabriele , Baroni Massimo , Bonelli Daniela , Clementi Sergio , Ebert Cynthia , Skagerberg Bert 
Published: October 2006

AbstractChemometric methods suitable for QSAR modelling, namely partial least squares (PLS) and multiple regression analysis (MRA), are compared in terms of their prediction abilities by means of the appropriate statistical parameter called standard deviation of errors of predictions (SDEP). The results show the reliability of the PLS approach and point out the risk of overfitting with MRA, which may give rise to unreliable predictions.
Multivariate Techniques for Parameter Selection and Data Analysis Exemplified by a Study of Pyrethroid Neurotoxicity
Authors: Ford Martyn G. , Livingstone D. J. 
Published: October 2006

AbstractA large number of molecular descriptors (70) were calculated for a series of pyrethroid insecticides using the techniques of computational chemistry. Because the set of descriptors contains considerable redundancy, it is necessary to reduce the size of the data matrix while retaining useful information. Various techniques are available for investigation and reduction of large data sets. Several of these methods have been employed and the results of the different strategies compared. It is concluded that there is no preferred method but that each technique has advantages to offer and is complementary.
Determination of Topological Equivalence in Molecular Graphs from the Topological State
Authors: Hall Lowell H. , Kier Lemont B. 
Published: October 2006

AbstractA method for computer perception of topological equivalence is presented along with consequences for analysis of molecular graphs and applications to SAR. This method is based on a new concept called the topological state of skeletal atoms. Topological equivalence is the molecular characteristic associated with structure equivalences within the molecular skeleton without regard to full three‐dimensional geometry. In this investigation, structure is represented by the chemical graph (hydrogen‐suppressed graph). Topological equivalence, the equivalence of skeletal atoms, is based upon numerical equality of the topological state values introduced in this method. The topological state value for an atom is defined in terms of three quantities: the number of skeletal paths terminating on that atom, the number of atoms in each path (graph separation), and a numerical expression for the chemical identity of each atom. Atom identity is encoded by the molecular connectivity valence delta value. Several algorithms for computation of topological state value are examined, all based on use of the geometric mean of the valence delta values of the atoms in each path. It is shown for a large number of molecules with a wide variety of structure types that proper topological equivalence perception is achieved by this method for several algorithm formulations. This formalism of topological state may prove highly useful as a characterization of the environment of skeletal atoms. The total topological index also introduced here appears to be a highly discriminating index of molecular graphs. Implications for structure‐activity studies are discussed and two example QSAR uses of the total topological index are presented: gas chromatographic retention index for alcohols and inhibition of T. mentagrohpytes by phenylpropylethers.
“Classical” and “Magnetic” Aromaticities as new Descriptors for Heteroaromatics in QSARs. PLS Prediction of Tetrahymena Pyriformis Growth Inhibition by Heteroaromatics
Authors: Ebert Cynthia , Katritzky Alan R. , Musumarra Giuseppe 
Published: October 2006

AbstractThe concentrations of heteroaromatics which inhibit growth of “Tetrahymena pyriformis” are tested for correlation with twelve measures of aromaticity for these compounds together with log P and the molecular connectivity. A two principal component (PC) model accounts for 65% of the total variance and demonstrates the significance of scales of magnetic aromaticity in general and of χM in particular, of log P and of molecular connectivity. PLS treatment using the three descriptors I′x, χM and log P explains 89% of the variance: a single parameter correlation with χM is almost as successful.The potential for the present method to predict toxicities of heterocycles is indicated.
A Differential Molecular Connectivity Index
Authors: Kier Lemont B. , Hall Lowell H. 
Published: October 2006

AbstractA differential molecular connectivity index, ΔmX, has been defined which is the difference between the simple and the valence connectivity indexes of the same order, m, is ΔmX = mX — mXv. The information contained in this index is largely electronic with contributions from adjacent alkyl fragments amounting to the size of m. The electronic information is a quantitation of the pi and lone pair electrons on that part of the fragment defined by m. The index is capable of modeling selected physical properties which are regiospecific within a molecule. Examples include NMR chemical shifts, gas phase basicities, ionization potentials and chromatographic retention indexes.
QSAR in Bradykinin Antagonists. Inhibition of the Bradykinin induced Contraction of the Isolated Rat Uterus and Guinea Pig Ileum
Authors: De Castro L. Felipe Pineda , Reißmann Siegmund 
Published: October 2006

AbstractQuantitative structure‐activity relationships (QSAR) in bradykinin antagonists with activity on rat uterus and/or guinea pig ileum were investigated by the Free‐Wilson method in the Fujita‐Ban approach. The substituent contributions to antagonist activity were calculated by multiple linear regression. The used QSAR model adequately describes the experimental data, so that the assumption about additivity and independence of the substituent contributions to the overall activity is valid. The obtained results allow a survey of the effect of different modifications on the antagonist potency. Information about the influence of various substitutions on the selectivity of the antagonists can be extracted from the comparison of the QSAR for both the tissues studied.
Quantitative Structure‐Activity Relationships in the Prediction of Penicillin Immunotoxicity
Authors: Bartlett Alison , Dearden John C. , Sibley Peter R. 
Published: October 2006

AbstractPenicillin antibiotics are one of the most important classes of pharmaceutical agents, both therapeutically and economically, in modern day usage. However a major clinical drawback is the incidence of immunologically mediated adverse reactions exhibited by the general population in response to their use.Using the techniques of classical QSAR we have produced statistically and predictively valid models which relate

the incidence of cutaneous rash induced by oral penicillins to the similarity in shape to benzyl penicillin (n = 14, r = 0.907).
the incidence of all subjective clinical adverse reactions induced by parenteral penicillins to the ClogP and Sterimol B2 parameters (n = 12, r = 0.940).
the incidence of gastro‐intestinal disruption induced by parenteral penicillins to the number of methyl groups in the acyl side chain substituent (n = 11, r = 0.882).
A Quantitative Structure‐Activity Relationship Study on Some Cholecystokinin Antagonists
Authors: Gupta Satya P. , Mulchandani Veena , Das Subharanjan , Subbiah Arun , Reddy D Narsimha , Sinha Jyoti 
Published: October 2006

AbstractA quantitative structure‐activity relationship (QSAR) study is made on three different series of cholecystokinin (CCK) antagonists, namely a series of 3‐(3‐indolylmethyl)‐1, 4‐benzodiazepines, a series of glutamic acid analogues, and a series of indole derivatives of quinazolinone. An analysis of this study leads to suggest that CCK antagonists primarily bind with the receptor through hydrogen bonds and/or hydrophobic interactions, and that this binding is further strengthened by the involvement of certain substituents in some secondary bindings through, most likely, dispersion interactions.
A CoMFA Model of Steric and Electronic Effects of Phosphorus Ligands
Authors: Steinmetz Wayne E. 
Published: October 2006

AbstractThe method of comparative molecular field analysis (CoMFA) has been applied to a series of 6 reactions involving a transition‐metal center and a series of substituted phosphine ligands. A CoMFA analysis of parameters used in classical QSAR including the Tolman cone angle and Brown's steric parameter ER has also been performed. Provided that the dataset of compounds is carefully chosen and is sufficiently large, CoMFA can be used in place of traditional QSAR methods which have employed Tolman cone angles and carbon‐13 chemical shifts as parameters. The CoMFA results show that steric and electronic factors have comparable weight in determining chemical reactivity in the types of reactions considered.
Using Artificial Neural Networks to Predict Biological Activity from Simple Molecular Structural Considerations
Authors: Burden Frank R. 
Published: October 2006

AbstractSome simple molecular structural considerations relating to atom type were used as the independent variable inputs to an artificial neural network with the dependent variables consisting of the physicochemical parameters molecular refractivity and hydrophobicity. The low root mean squared error in each case was sufficiently low for the further mapping of biological activity to be attempted. A set of 236 dihydrofolate reductase inhibitors, for which the biological activity was known, was fitted in a similar manner and again producing a low root mean squared error. It is concluded that neural networks can be used to predict biological activity, within a series of closely related molecules, from molecular structural considerations alone so saving much effort in synthesis and in vivo testing with new candidate molecules.
Quantitative Structure ‐ Activity Relationship Studies on Benzodiazepine Receptor Binding of Some Nonbenzodiazepine Series of Ligands
Authors: Gupta S. P. , Paleti Anitha 
Published: October 2006

AbstractQuantitative structure ‐ activity relationship (QSAR) studies have been performed on some non‐benzodiazepine series of benzodiazepine receptor (BZR) ligands, namely a series of thienylpyrazologuinolines and a series of imidazoquinoxalines. Studies reveal the merits and demerits of the substituents and their physicochemical properties in each case, in addition to the essential requirements for the binding for each type of ligand.