TARGET INDEPENDENT ASSAY SYSTEMS AND METHODS

Abstract: Pre-screened libraries, such as pre-screened chemical composition libraries useful for drug screening, are generated using target independent assays. The methods typically involve screening of master libraries in microfluidic devices for effects that are correlated to one or more target independent parameter. Also included are multi-module workstations, such as microfluidic workstations,and integrated systems, for performing target independent assays.

Description: TARGET INDEPENDENT ASSAY SYSTEMS AND METHODS CROSS REFERENCE TO RELATED APPLICATIONS This application claims priority to and benefit of provisional application USSN 60/133,919, filed May 13, 1999; USSN 60/164,218, filed November 9, 1999; and USSN 60/195,159 filed April 6, 2000, pursuant to 35 USC 119 (e) and any other applicable statute or rule. COPYRIGHT NOTICE Pursuant to 37 C.F.R. 1.71 (e), Applicants note that a portion of this disclosure contains material which is subject to copyright protection. The copyright owner has no objection to the facsimile reproduction by anyone of the patent document or patent disclosure, as it appears in the Patent and Trademark Office patent file or records, but otherwise reserves all copyright rights whatsoever. BACKGROUND OF THE INVENTION A great deal of research and development effort has been spent in attempting to expedite the process of drug discovery. Areas of major research have included development of combinatorial chemistry techniques that facilitate the generation of large numbers of different compounds which are then evaluated to ascertain whether any of the generated compounds have pharmacologically important activities. Obviously, as the number of compounds to be screened has increased, there has been a corresponding need to enhance the speed and throughput of screening processes. Numerous methods have been developed to expedite screening assays. Typically, this has involved the use of complex and expensive robotic fluid and plate handling systems to perform large numbers of screening assays. Once a compound is screened and demonstrates potential activity, that compound can be rescreened to determine the precise nature of its activity, and to screen it for secondary effects, e.g., toxicological effects, bioavailability, and the like. A variety of assays are typically performed subsequent to an initial activity-screening assay (or target dependent assay) in pharmaceutical research to assess whether an active compound will be useful in vivo. Typically, a number of in vivo activities can affect whether a potential drug might ultimately be effective, including the toxicity of the compound, the non-specific binding of the compound to other elements, the passage of the compound through various biological barriers, and the like. These parameters are evaluated in secondary or "target independent" assays. In general, target independent assays are performed in pharmaceutical research following identification of a potential lead compound. This is typically due to the high cost of reagents for performing these assays. In order to conserve costs and expedite drug development, it would be desirable to be able to perform both the primary screening assay and the secondary, or target independent assays, as rapidly, inexpensively and as early as possible. The present invention addresses these and a variety of other needs. SUMMARY OF THE INVENTION The present invention provides methods and assays for generating or designating large chemical composition libraries that are substantially devoid of compounds that have a undesirable effect in one or more target independent assay. Methods for evaluating large numbers of chemical compositions (including individual compounds, mixes of compounds, etc.) in cost-effective, high throughput assay systems suitable for screening libraries prior to performing target dependent assays are provided. The assays of the invention are performed sequentially, or simultaneously, on "parental" or "master" libraries which are typically in excess of 1000, 10,000, 100,000, or 1,000,000 compositions, or on successively screened libraries depending therefrom. The pre-screened libraries can be physically separated from the master libraries, thereby generating pre-screened libraries, or can simply constitute designated members of the master library. Pre-screened libraries evaluated in one or more target independent assay by the methods of the invention are an aspect of the invention. The pre-screened libraries provided comprise in excess of 100, 1000, 10,000, 100,000, or 1,000,000 compositions that exhibit a desired activity in one or more target independent assay, and/or are substantially devoid of compositions that exhibit an undesired effect in the target independent assays. In some embodiments, the libraries are arrayed in multiwell plates or other array formats. In some embodiments, the libraries are represented by one or more data sets that correlate results of one or more target independent assay with locations in the master library array. Generally, such data sets are stored in a computer readable medium. The invention provides assays that evaluate effects correlated with target independent parameters such as serum half-life, cellular uptake, oral availability, cellular or organismal viability, cellular or organismal toxicity, apoptosis, cellular adhesion, target independent receptor binding or activation, target independent enzyme modulation activity, target independent protein modulation activity, target independent nucleic acid modulation activity, glucuronide conjugation modulation, sulfate conjugation modulation, amino acid conjugation modulation, acylation modulation, methylation modulation, transcription modulation, translation modulation, protein folding modulation, modulation of cell growth, membrane permeability, membrane integrity, metabolic stability, thermal stability, solubility, solution viscosity, solution turbidity, acidity, basicity, RedOx state, superoxide secretion, lipid peroxidation, octanol/water partitioning, precipitation in one or more buffers, or the like. Target independent assays that evaluate the binding of chemical compositions on serum proteins are provided by the methods of the invention. One example of a protein of interest is Human Serum Albumin (HSA). Due to the ubiquitous nature of HSA in human systems (and similarly, other serum albumins in other mammalian systems), the interaction between HSA and a composition of interest can have a considerable effects, e.g., on composition availability in vivo. Typically, one can monitor composition binding to HSA, e.g., by determining the composition's ability to inhibit binding of a labeled material to HSA in vitro. Thus, in one embodiment, where the serum protein is HSA, the ability of a selected compound to bind HSA is measured as a function of its inhibition of binding of a fluorescent dye such as dansyl-1-sulfonamide or dansyl sarcosine to HSA. The invention also provides target independent assays that evaluate the inhibition of an enzyme by components of a chemical composition library. Target independent assays of the invention measure the effect of a composition on enzymes including: glutathione-s-transferases, proteases, peptidases, kinases, phosphatases, G proteins, ATPases, cytochrome P450s, ligases, carboxylesterases, epoxide hydrolases, aza- or nitro-reductases, carbonyl reductases, disulfide reductases, sulfoxide reductases, quinone reductases, alcohol dehydrogenases, aldehyde dehydrogenases, aldehyde oxidases, xanthine oxidases, monoamine or diamine oxidases, prostaglandin sythases, flavin-monooxygenases, and dehalogenases. In some embodiments, effects on enzymes are evaluated using fluorescent or fluorogenic substrates In preferred embodiments, the target independent assays are performed in a microfluidic device. In some embodiments, the microfluidic device comprises a pipettor element. In another embodiment, the target independent assay is performed by flow cytometry in a microfluidic cell-focusing device. In one embodiment, the flow cytometry distinguishes between live cells and dead cells. Flow cytometry methods that distinguish between live cells and dead cells are based on differential permeability or binding to a fluorescent dye or dye conjugate, such as calcein AM, BCECF AM, ethidium bromide, propidium iodide, a cationic dye, a cationic membrane permeable dye, a neutral dye, a membrane permeable neutral dye, an anionic dye, an anionic membrane permeable dye. In alternative embodiments, the target independent assay evaluates the effect of a composition on calcium flux across the membrane of a cell preloaded with a fluorescent calcium indicator. In some embodiments, the master library is arrayed in one or more multiwell plate(s), on a solid substrate such as a membrane or card, or in a bead matrix. Data sets correlating the results of one or more target independent assay with one or more members of the master library array are compiled in some embodiments. In some cases, the data set correlates results of multiple target independent assays with members of the master library array. The invention further provides methods and devices for performing target independent assays in a multi-module workstation. The multi-module workstations of the invention include screening modules for performing the target independent assays, substrates corresponding to composition libraries, robotic mechanisms connecting the screening modules, and, e.g., a computer assisted control system for controlling the movement of substrates by the robotic mechanism, or alternatively of the robotic mechanism between or within the substrates. In some embodiments, the screening modules are configured to perform target independent assays such as flow cytometry assays, assays which evaluate the effect of a selected composition on a biochemical system, assays which measure a calcium flux across a cell membrane, assays which evaluate binding of a serum protein, assays which evaluate binding to Human Serum Albumin, assays which evaluate the effect of a selected composition on an enzyme, and the like. In preferred embodiments, the screening modules comprise microfluidic devices. Substrates include, e.g., multiwell plates, solid substrates or bead arrays. The robotic mechanism includes, for example, a conveyor belt, a slide mechanism, rollers, a cable and pulley mechanism, a robotic armature, or any combination thereof. The computer optionally includes instructions sets for movement of substrates, movement of the robotic mechanism, movement of the screening modules and/or selection of library members, etc., as well as, e.g., data sets correlating the results of the target independent assays with members of the library array, and a user interface for programming inputs into the system. The invention additionally provides for use of any of the pre-screened libraries, or component compositions, in a target dependent assay. Kits for performing one or more target independent and/or target dependent assay to produce the pre-screened libraries of the invention are also a feature of the invention. BRIEF DESCRIPTION OF THE FIGURES Figure 1: Panels A and B provide microfluidic channel configurations useful for performing target independent assays. Figure 2: A microfluidic channel configuration for performing target independent assays. Figure 3: Panel A provides an HSA-drug binding plot. Panel B provides a plot of inhibition vs. phenylbutazone concentration. Panel C provides data of HSA binding to six drugs. Figure 4: Panel A provides an overview of glutathione S-transferase (GST) reactions. Panel B illustrates useful substrates for GST assays and Panel C provides results of such assays performed in microfluidic devices. Figure 5: Protease assay results. Figure 6: Panel A illustrates mobility shifts in protein kinase assays. Panel B provides protein kinase mobility shift data. Panel C provides a Lineweaver-Burk plot for determination of kinetic data in a PKA assay. Panel D provides PKA inhibitor data and Panel E provides data obtained in a microfluidic sipper device. Figure 7: Panel A provides phosphatase assay data from a microfluidic assay. Panel B provides raw data and Panel C illustrates determination of K, from the raw data. Figure 8: Panel A is a schematic illustration of a G-protein coupled receptor cell based assay which is optionally performed in a microfluidic device as illustrated in Panel B. Panels C through F provide data from a G-protein coupled receptor cell based assay performed in a microfluidic device. Figure 9: A multi-module workstation useful in performing multiple target independent assays, e.g., to produce a pre-screened library. DETAILED DESCRIPTION INTRODUCTION The high cost of drug development is due in large part to the high attrition rate for drugs entering preclinical and clinical development. In addition to criteria such as toxicity and performance, lead compounds can exhibit desirable characteristics with respect to such properties as absorption, bioavailability, metabolism and the like. The ability to focus research and development efforts exclusively on chemical compounds which meet specified criteria in assays which are predictive of the biological events related to absorption, bioavailability, and metabolism, is of significant interest in the pharmaceutical industry. In the past, the cost of reagents (e.g., compounds of interest) associated with performing a large number of secondary screening assays (e.g., to test for absorption, bioavailability, metabolism and the like) was prohibitive. Therefore, only potentially active compounds were previously subject to secondary screens. Thus, in classical compound screening methods, a round of primary screens (i.e., screens for an activity of interest) were followed by a round of secondary screens performed on hits (compounds identified as having the activity of interest) from the primary screen. Thus, typically, separate rounds of primary screening were followed by separate rounds of secondary screening. For example, many large pharmaceutical companies have enormous libraries of compounds which are typically subject to primary assay screens to identify hits, with each of these hits being re- screened in each secondary assay considered relevant. In contrast, the present invention provides methods for producing large chemical composition libraries which are pre-screened for secondary activities of interest, providing large libraries which meet selected criteria. These pre-screened libraries are then screened for activities of interest. Thus, the present invention provides methods of pre- screening libraries, the pre-screened libraries resulting from practicing the methods, integrated systems for practicing the methods and databases of pre-screened compositions. For example, the chemical composition libraries of the invention are pre- screened in assays predictive of biologically relevant characteristics prior to their evaluation as potential drug leads. For purposes of this disclosure, "pre-screened" indicates that a chemical composition library, or collection of chemical compounds, is evaluated in one or more assay which evaluates properties correlated with, e.g., clinical performance or other activity criteria, rather than with properties specific to the therapeutic target of interest. Such an assay is a "target independent assay," that is, an assay that screens for a general property other than the activity of primary interest for a particular compound. In contrast, an assay that evaluates impact of a composition, or a library of compositions, on a biological or other system, e.g., related to its therapeutic role, is designated a "target dependent assay." It will be appreciated that the terms "target independent" and "target dependent" are relative with respect to the functional context of the target or other assay components. For example, a kinase assay can be a target dependent assay when the subject kinase of the assay is the target of, e.g., modulation by the compound or components of the library. In contrast, a kinase assay used to determine, e.g., effects on global phosphorylation status, unrelated to the target (which, in some cases, is itself a kinase) is a target independent assay. The methods of the invention provide the significant benefit that a particular target independent assay is performed once for a given library, rather than after each and every target dependent assay. Basic methods and systems for performing these assays are described in U.S. Patent No. 5,942,443, issued August 24, 1999 and U.S. Patent Application Nos. 08/883,638, filed June 27, 1997; 09/173,469, filed October 14, 1998, and 09/093,489, filed June 8, 1998, which are incoφorated herein by reference for all purposes. Chemical composition libraries are composed of a collection of chemical compositions or compounds. Such libraries can include a wide variety of different compounds, including chemical compounds, mixtures of chemical compounds, e.g., polysaccharides, small organic or inorganic molecules, biological macromolecules, e.g., peptides, proteins, nucleic acids, or an extract made from biological materials such as bacteria, plants, fungi, or animal cells or tissues, or naturally occurring or synthetic compositions. A "parental library" or a "master library" refers to a library, the members of which are to be evaluated for their ability to affect a particular biochemical system. By pre- screening these libraries, one can effectively prioritize further screening of those members of the library that have positive or adverse effects in these target independent assays. Thus, the pre-screened libraries can be selected for compounds that have positive effects in these target independent assays. Typically, the master libraries will have in excess of 1000, more typically in excess of 10,000, and often in excess of 100,000 or even 1,000,000 or more members prior to the pre-screening assay, with the number of members being reduced, e.g., by typically at least 10%, often 20 %, in some cases 50%, and sometimes 90% or more. Rephrased, target dependent assays can focus only on 90%, 80%, 50%, and potentially after several target independent assays, as little as 10% or less of the initial or master library population. Master or pre-screened libraries can include arrays having one or more compound type per location in the array, e.g., the libraries can be arrayed as sets of single compounds or as arrays of mixtures of compounds. For ease of decon volution (determination as to which component(s) are relevant to a desired activity), mixtures can include about 1,000 compound types or less, typically about 100 compound types or less, generally about 10 compound types or less, and often about 5 or fewer compound types. In addition to weeding out less desirable members from the master library (whether physically, or simply by noting the location or presence of positive hits in the secondary assay), secondary screening assays can also be used as a basis to add additional members for consideration into the pre-screened library. For example, where compounds of a given general structure are active in the secondary screen, additional structurally related library members can be generated, tested and incoφorated into the pre-screened library. Finally, in some aspects, entire master libraries are screened regardless of the activity of compounds in secondary screening assays. Positive hits which are also active in secondary assays are, of course, potential lead compounds. However, compounds which are negative in secondary screening assays, but positive in target dependent assays can be converted into potential lead compounds. For example, in some cases, hits in a target dependent assay can be modified for improved secondary properties, without eliminating activity in the target dependent assay (e.g., by chemical modification of the relevant composition). Information from target independent library screens can be used in modifying such potential lead compounds, and, of course, libraries can include such modified compounds for additional secondary screening assays. As noted above, prior to the present invention, the scale, and hence the cost of pre-screening chemical compound libraries in target independent assays prior to evaluating their effects in a target dependent assay, has been prohibitively large. Typically, a library of chemical compositions is evaluated in a target dependent assay to determine its potential as a drug lead. Promising lead candidates are then evaluated for such parameters as serum half-life, membrane permeability, toxicity, enzyme inhibition, and the like. This approach maximizes the number of potential leads identified, but is accompanied by a relatively high level of attrition and, therefore, high cost per potential lead. It is also extremely expensive in terms of reagent usage, as many leads do not meet the criteria of secondary assay screens. As noted, the present invention provides libraries which have been pre-screened in target independent assays, and are therefore, substantially devoid of compounds which have undesirable properties in target independent assays. Accordingly, a high proportion of the compositions which are identified have the characteristics of successful drug candidates, e.g., high bioavailability, low toxicity, stability, etc. By utilizing the pre-screened libraries of the invention, downstream costs are minimized, as fewer identified leads are eliminated during the later stages of development, which are associated with higher development costs. The libraries of the invention are produced by evaluating large collections of chemical compositions in target independent assays in a high throughput format. Such high throughput formats can be multiwell plate based, e.g., in 96-well, 384-well, 1,536-well plates, or solid support based such as on pin arrays. In preferred embodiments, the high throughput format includes performing one or more assay in one or more microfluidic device. To facilitate the evaluation of a large collection of chemical compositions in one or more target independent (and/or target dependent) assays, the chemical compositions are preferably arranged in a logically accessible set, i.e., an "array." The logical organization of arrays can be based on spatial relationships of array members, (i.e., where the arrays are in a gridded arrangement), or can be in an arbitrary arrangement that can be corresponded to a look-up table to provide equivalency information. Such arrays include master library arrays, as well as arrays of libraries that have been pre-screened in one or more than one target independent assay. Library arrays further include pre-screened libraries which have also been evaluated in one or more target dependent assay. It is also worth noting that, in addition to placing single compound members in an array, array members can alternatively have mixtures of compounds. For example, where an array member representing a mixture of compounds is tested, the member can be further deconvoluted to identify which of the constituents of the mixture are relevant for activity. For example, if the components of the array member are known, they can be separately screened following identification of activity of the mixture. The library arrays of the invention can include any material structure in which the physical substance comprising the chemical compositions can be maintained and accessed, e.g., multi-well plates, pin arrays, bead arrays, test tube arrays, etc. For example, in one set of embodiments, samples are arrayed and accessed by microfluidic systems as described, e.g., in "MICROFLUIDIC SAMPLING SYSTEM AND METHODS," U.S. Patent No. 6,042,709 to Parce et al. A number of additional useful library-microfluidic systems are set forth in "CLOSED-LOOP BIOCHEMICAL ANALYZERS" WO98/45481. Additional details regarding library systems and microfluidic systems are set forth in "ULTRA HIGH THROUGHPUT SAMPLING AND ANALYSIS SYSTEMS AND METHODS" to Wolk et al. USSN 60/042,709, filed January 6, 2000. In other cases, it is desirable to maintain a data set which correlates the results of one or more target independent assays with positions within a library array. In the latter case, the data set is typically stored in a computer readable medium and is optionally produced and/or accessed via an integrated system that performs the assays in question. In alternate embodiments, data storage and assay performance are separately maintained. The data set can correlate the results of a single target independent assay, multiple target independent assays, and/or one or more target dependent assays with positional information identifying individual members of a chemical composition library array. The array can be physically arranged in one multiwell plate, pin array or bead array or the like; in a plurality of multiwell plates, pin arrays or bead arrays or the like; or in a combination thereof. One, or more than one, library member can be maintained in each position of the array. Furthermore, the data set or sets corresponding to a master library, and any number of pre- screened libraries, can coincide with a single physical library array, or with any number of distinct and separate library arrays. For example, a chemical composition library in excess of 100,000 members constituting a master library can be arrayed in a set of multiwell plates, e.g., about 66 x 1536 well plates, about 261 x 384 well plates, or about 1004 x 96 well plates, or various combinations thereof. A data set that correlates the composition of each library member with its position within the array is established, typically via the integrated system of the invention. The library is then evaluated in a target independent assay of the invention, and the results are correlated with positions within the array. Additional target independent and or target dependent assays are performed, sequentially or simultaneously, and the results correlated with positions within the library array. Thus, one or more pre-screened library of the invention coincides physically with one or more master library of the invention. Alternatively, prior to the performance of any sequential assay, selected library members can be transferred and or replicated in a physically and spatially distinct library array. TARGET INDEPENDENT ASSAYS Target independent assays are, in general, in vitro model systems for measuring the effect of a chemical compound on a biological or biochemical system or molecule, regardless of the specific activity for which the compound is sought. In the pharmaceutical industry, target independent assays are used to evaluate potential lead compounds, regardless of whether the lead compounds are chemical compositions or biochemical compositions or whether they are naturally occurring, isolated or synthetic compositions. The present invention provides methods for producing chemical composition libraries that have been evaluated for their effects in one or more target independent assay. Thus, the libraries produced by the methods herein fit designated criteria reflecting their effects in biochemical systems. The members, or components, of the libraries provide a pool of potential lead candidates that are known to be substantially devoid of negative effects correlated with poor performance in pre-clinical or clinical trials, and, therefore, with failure as therapeutic reagents. Target independent assays that measure such parameters as serum half-life, cellular uptake, oral availability, cellular or organismal viability, cellular or organismal toxicity, apoptosis, cellular adhesion, target independent receptor binding or activation, a target independent enzyme modulation activity, a target independent protein modulation activity, a target independent nucleic acid modulation activity, glucuronide conjugation modulation, sulfate conjugation modulation, amino acid conjugation modulation, acylation modulation, methylation modulation, transcription modulation, translation modulation, protein folding modulation, modulation of cell growth, membrane permeability, membrane integrity, metabolic stability, thermal stability, solubility, solution viscosity, solution turbidity, acidity, basicity, RedOx state, superoxide secretion, lipid peroxidation, octanol/water partition, and precipitation in one or more buffers can be performed in the context of the present invention. Indeed, any biochemical assay, either known in the art, or subsequently developed to address specific applications, is suitable for the methods of the present invention, provided that it can be performed in high-throughput assays. For example, cellular toxicity can be evaluated by assays such as differential binding of vital or fluorescent dyes, evaluated by flow cytometry, that distinguish between live and dead cells. Cultured cells, such as the human hepatocellular carcinoma cell line, Hep G2, or other suitable cells, are exposed to compositions of a chemical compound library, and simultaneously or subsequently, incubated with a dye, e.g., propidium iodide, that demonstrates differential staining of dead versus live cells. (Dead cells are PI bright and live cells are PI dim). The staining is then evaluated and the proportion of dead cells is calculated to determine compositions that exhibit an acceptable level of toxicity, that is, which result in acceptable ratios of dead to live cells. Bioavailablilty of a therapeutic composition is influenced by, among other things, solubility, stability in solution, water/lipid partition coefficients, intestinal degradation via brush border enzymes and proteases (e.g., as occurs in the gut in vivo) and binding to serum proteins. These parameters are the subject of target independent assays. For example, the methods of the invention measure the binding of members of a chemical composition library to a serum protein, such as human serum albumin (HSA). Binding is, for example, measured as a function of the ability of a composition to interfere or inhibit binding of HSA by one or more fluorescent dyes (e.g., dansyl-1-sulfonamide, dansyl sarcosine). The target independent assays of the invention also evaluate binding and/or activation of cellular or reconstituted receptors. Examples of such assays include cellular and in vitro assays. Cellular assays measure binding as a function of, e.g., cellular calcium flux. In vitro assays can be based on competitive binding with a labeled ligand or other marker molecule, e.g., a dye. Examples of microfluidic cellular assays utilizing dyes are found, e.g., in U.S. Patent Application Nos. USSN 09/416,288, filed October 12, 1999; and USSN 60/158,323, filed October 8, 1999. Other target independent assays measure the effect, e.g., inhibition, of a composition on the catalytic activity of an enzyme. Enzymes are typically selected either because they play an essential or important cellular housekeeping role, or because they represent classes of enzymes that play a significant role in cellular homeostasis, growth, differentiation, or division. Such enzymes include: glutathione-s-transferases, proteases, peptidases, kinases, phosphatases, G proteins, ATPases, cytochrome P450s, ligases, carboxylesterases, epoxide hydrolases, aza- or nitro-reductases, carbonyl reductases, disulfide reductases, sulfoxide reductases, quinone reductases, alcohol dehydrogenases, aldehyde dehydrogenases, aldehyde oxidases, xanthine oxidases, monoamine or diamine oxidases, prostaglandin sythases, flavin-monooxygenases, and dehalogenases. Inhibition, or conversely, enhancement, of enzymatic activity by a chemical composition of these and other enzymes can be evaluated by numerous well-established assays known to those of skill in the art. TARGET DEPENDENT ASSAYS In contrast to target independent assays, "target dependent assays" evaluate the effects of a chemical composition, or library of compositions on a particular pharmaceutical screening target, e.g., where an effect on that target is the desired result of the drug that is being sought. A target can be any biochemical molecule that plays a role in a biochemical pathway mediating a process within an organism. As such, a target influences, any, or many, biological process involved in the organism's health or disease. A therapeutic reagent is selected to have a desired effect on the target, or on the pathway or process that involves the target. To evaluate the effect of potential drug leads, e.g., chemical compositions, target dependent assays are employed. Any in vitro, cellular, or in vivo assay that is used to determine the effect of a chemical composition on a potential therapeutic target is considered a target dependent assay for the puφoses of the invention. Furthermore, in vitro or cellular assays that measure an aspect of the in vivo effect of a composition on a target are also considered target dependent assays. Target dependent assays are distinguished from target independent assays, not strictly on the basis of the type of assay, or biochemical molecule (or pathway) that they evaluate, but rather on the relationship of the biochemical molecule to the potential therapeutic use of the chemical compositions being evaluated. That is, the target dependent assay evaluates the biochemical effect of the molecule, e.g., on a disease target, while the independent assay evaluates the effect on secondary considerations which affect, e.g., efficacy, bioavailability, and/or toxicity, etc.. Thus, target independent assays are generally not tied to any particular disease pathology, but instead can include systems or assays that are operative in normal healthy systems. The subject of a target dependent assay can be, e.g., a receptor, an enzyme, a signaling molecule, a membrane protein, a blood protein, a structural protein, a ligand, a substrate, cells, nucleic acids (DNAs, RNAs, etc.), membrane fractions or the like. Both target independent assays, and target dependent assays can be performed in high throughput formats such as multi-well plates and microfluidic devices and combinations thereof. In the present invention, target dependent assays optionally are performed on the pre-screened libraries. It will be apparent that whether the target dependent assay is performed before or after conducting one or more target independent assays is not of critical importance. However, in general, it will be most efficient and therefore least costly, to generate pre-screened libraries that have been evaluated for several target independent parameters, and then repeatedly using this valuable resource as the basis for subsequent target dependent assay screening projects. HIGH THROUGHPUT SCREENING FORMATS Prior to the present invention, the production of a pre-screened library evaluated in multiple target independent assays prior to identification of potential drug leads was prohibitively expensive. While those of skill in the art have long known the basic assays, the capacity to so reduce the scale of the assays as to make them economically desirable as pre-screening tools has been lacking. Depending upon the particular embodiment being practiced, the chemical composition libraries can be provided, e.g., injected, free in solution, or can be attached to a carrier, or a solid support, e.g., beads. In preferred embodiments, the chemical composition libraries (which can be single compounds or compound mixtures) are arranged in an organized matrix or array. An array can be of compositions in solution, e.g., microtiter plates, on a solid membrane, in a bead matrix or other existing formats. A number of solid supports are suitable for the immobilization of the chemical compositions, including polymers, plastics, agarose, cellulose, dextran, carboxymethyl cellulose, polystyrene, polyethylene glycol (PEG), filter paper, nitrocellulose, ion exchange resins, plastic films, glass beads, polyaminemethylvinylether maleic acid copolymer, amino acid copolymer, ethylene-maleic acid copolymer, nylon, silk, etc. In recent years, microtiter plates have become a standard format for the performance of high throughput screening assays. Standard microtiter plates are available with 96, 384 or 1536 wells, although other commonly used number of wells include 3456 and 9600. Well volumes range between 500 nanoliters to over 200 microliters, depending on well depth and cross sectional area. Microtiter plates are typically selected for compatibility with current automated loading and robotic handling systems, with an 86 mm by 129 mm dimension being an industry standard. Alternative formats have been proposed, e.g., U.S. Patent No. 5,989,835, which are equally suitable for the methods of the present invention. Other applicable systems are described, e.g., in "MICROFLUIDIC SAMPLING SYSTEM AND METHODS," U.S. Patent No. 6,042,709 to Parce et al. A number of additional useful library-microfluidic systems are set forth in "CLOSED-LOOP BIOCHEMICAL ANALYZERS" WO98/45481. Additional details regarding library systems and microfluidic systems are set forth in "ULTRA HIGH THROUGHPUT SAMPLING AND ANALYSIS SYSTEMS AND METHODS" to Wolk et al. USSN 60/042,709, filed January 6, 2000. Some assays, in particular those which involve detection of a product by autoradiography, liquid scintillation counting, luminometry and the like, are preferably performed by transferring one or more assay component to a filter medium adapted for use in a multiwell, e.g., microtiter format (see e.g., U.S. Patent No. 5,939,024). The assays of the present invention, including target independent and target dependent assays, can be performed in the microtiter plate format described above. For some assays, appropriate selection of well dimensions, and reagents makes the microliter scale required in such formats feasible for generating the pre-screened libraries of the invention. However, in many cases, the cost remains prohibitive. Microfluidic Devices In preferred embodiments, the target independent assays (and/or target dependent assays) of the present invention are carried out in microfluidic devices or "microlaboratory systems," which allow for integration of the elements required for performing the assay, automation, and minimal environmental effects on the assay system, e.g., evaporation, contamination, operator error. These microfluidic devices provide for integratability with e.g., microwell plates, solid substrates, bead arrays and the like. For example, PCT/US 98/06723, filed April 3, 1998, provides examples of formats for integrating microfluidic devices with microtiter plates, solid substrates and the like. A number of devices which can be adapted for use in carrying out the assay methods of the invention have been described by the inventors and their coworkers. These devices are described in various PCT applications and issued U.S. Patents by the inventors and their coworkers, including U.S. Patent Nos. 5,699,157 (J. Wallace Parce) issued 12/16/97, 5,779,868 (J. Wallace Parce et al.) issued 07/14/98, 5,800,690 (Calvin Y.H. Chow et al.) issued 09/01/98, 5,842,787 (Anne R. Kopf-Sill et al.) issued 12/01/98, 5,852,495 (J. Wallace Parce) issued 12/22/98, 5,869,004 (J. Wallace Parce et al.) issued 02/09/99, 5,876,675 (Colin B. Kennedy) issued 03/02/99, 5,880,071 (J. Wallace Parce et al.) issued 03/09/99, 5,882,465 (Richard J. McReynolds) issued 03/16/99, 5,885,470 ( J. Wallace Parce et al.) issued 03/23/99, 5,942,443 (J. Wallace Parce et al.) issued 08/24/99, 5,948,227 (Robert S. Dubrow) issued 09/07/99, 5,955,028 (Calvin Y.H. Chow) issued 09/21/99, 5,957,579 (Anne R. Kopf-Sill et al.) issued 09/28/99, 5,958,203 (J. Wallace Parce et al.) issued 09/28/99, 5,958,694 (Theo T. Nikiforov) issued 09/28/99, and 5,959,291 ( Morten J. Jensen) issued 09/28/199; and published PCT applications, such as, WO 98/00231, WO 98/00705, WO 98/00707, WO 98/02728, WO 98/05424, WO 98/22811, WO 98/45481, WO 98/45929, WO 98/46438, and WO 98/49548, WO 98/55852, WO 98/56505, WO 98/56956, WO 99/00649, WO 99/10735, WO 99/12016, WO 99/16162, WO 99/19056, WO 99/19516, WO 99/29497, WO 99/31495, WO 99/34205, WO 99/43432, and WO 99/44217. Bead arrays in microfluidic systems are described, e.g., in USSN 09/510,626, "Manipulation of Microparticles in Microfluidic Systems," by Mehta et al. However, it will be recognized that the specific configuration of these devices will generally vary depending upon the type of assay and/or assay orientation desired. For example, in some embodiments, the screening methods of the invention can be carried out using a microfluidic device having two intersecting channels, or microchannels. For more complex assays or assay orientations, multichannel/intersection devices may be employed. The small scale, integratability and self-contained nature of these devices allows for virtually any assay orientation to be realized within the context of the microlaboratory system. For example, pioneering technology providing cell based microscale assays are set forth in Parce et al. "High Throughput Screening Assay Systems in Microscale Fluidic Devices" WO 98/00231 and, e.g., in 60/128,643 filed April 4, 1999, entitled "Manipulation of Microparticles In Microfluidic Systems," by Mehta et al. Complete integrated systems with fluid handling, signal detection, sample storage and sample accessing are available. For example, Parce et al. "High Throughput Screening Assay Systems in Microscale Fluidic Devices" WO 98/00231 provide pioneering technology for the integration of microfluidics and sample selection and manipulation. Commercial products which utilize microscale systems include the HP/Agilent Technologies HP2100 and the Caliper HTS system (Caliper Technologies, Mountain View, California). In general, cells, enzymes, receptors, substrates, library members and other elements can be flowed in a microscale system by electrokinetic (including either electroosmotic or electrophoretic) techniques, or using pressure-based flow mechanisms, or combinations thereof. Cells in particular are desirably flowed using pressure-based flow mechanisms. Pressure forces can be applied to microscale elements to achieve fluid movement using any of a variety of techniques. Fluid flow (and flow of materials suspended or solubilized within the fluid, including cells or other particles) is optionally regulated by pressure based mechanisms such as those based upon fluid displacement, e.g., using a piston, pressure diaphragm, vacuum pump, probe or the like to displace liquid and raise or lower the pressure at a site in the microfluidic system. The pressure is optionally pneumatic, e.g., a pressurized gas, or uses hydraulic forces, e.g., pressurized liquid, or alternatively, uses a positive displacement mechanism, i.e., a plunger fitted into a material reservoir, for forcing material through a channel or other conduit, or is a combination of such forces. In other embodiments, a vacuum source is applied to a reservoir or well at one end of a channel to draw the suspension through the channel. Pressure or vacuum sources are optionally supplied external to the device or system, e.g., external vacuum or pressure pumps sealably fitted to the inlet or outlet of the channel, or they are internal to the device, e.g., microfabricated pumps integrated into the device and operably linked to the channel. Examples of microfabricated pumps have been widely described in the art. See, e.g., published International Application No. WO 97/02357. Hydrostatic, wicking and capillary forces can also be used to provide pressure for fluid flow of materials such as cells. See, e.g., "METHOD AND APPARATUS FOR CONTINUOUS LIQUID FLOW IN MICROSCALE CHANNELS USING PRESSURE INJECTION, WICKING AND ELECTROKINETIC INJECTION," by Alajoki et al., USSN 09/245,627, filed February 5, 1999. In these methods, an adsorbent material or branched capillary structure is placed in fluidic contact with a region where pressure is applied, thereby causing fluid to move towards the adsorbent material or branched capillary structure. Mechanisms for reducing adsoφtion of materials during fluid-based flow are described in "PREVENTION OF SURFACE ADSORPTION IN MICROCHANNELS BY APPLICATION OF ELECTRIC CURRENT DURING PRESSURE- INDUCED FLOW" filed 05/11/1999 by Parce et al., USSN 09/310,027. In brief, adsoφtion of cells, serum proteins, enzymes, substrates, test compounds and other materials to channel walls or other microscale components during pressure-based flow can be reduced by applying an electric field such as an alternating current to the material during flow. Mechanisms for focusing cells and other components into the center of microscale flow paths, which is useful in increasing assay throughput by regularizing flow velocity is described in "FOCUSING OF MICROPARTICLES IN MICROFLUIDIC SYSTEMS" by H. Garrett Wada et al., USSN 60/134,472, filed May 17, 1999. In brief, cells are focused into the center of a channel by forcing fluid flow from opposing side channels into the main channel comprising the cells, or by other fluid manipulations. Diffusible materials such as unbound or unreacted substrates are also optionally washed from cells as described by Wada et al. during flow of the cells, i.e., by sequentially flowing buffer into a channel in which cells are flowed and flowing the buffer back out of the channel. In an alternate embodiment, microfluidic systems can be incoφorated into centrifuge rotor devices, which are spun in a centrifuge. Fluids and particles travel through the device due to gravitational and centripetal/centrifugal pressure forces. One method of achieving transport or movement of substrates, ligands, library members, and even cells (particularly substrates and library members) through microfluidic channels is by electrokinetic material transport. "Electrokinetic material transport systems," as used herein, include systems that transport and direct materials within a microchannel and/or chamber containing structure, through the application of electrical fields to the materials, thereby causing material movement through and among the channel and or chambers, i.e., cations will move toward a negative electrode, while anions will move toward a positive electrode. For example, movement of fluids toward or away from a cathode or anode can cause movement of receptors, enzymes, serum proteins, cells, library members, etc. suspended within the fluid. Similarly, the receptors, enzymes, serum proteins, cells, library members, etc. can be charged, in which case they will move toward an oppositely charged electrode (indeed, in this case, it is possible to achieve fluid flow in one direction while achieving particle flow in the opposite direction). In this embodiment, the fluid can be immobile or flowing and can comprise a matrix as in electrophoresis. In general, electrokinetic material transport and direction systems also include those systems that rely upon the electrophoretic mobility of charged species within the electric field applied to the structure. Such systems are more particularly referred to as electrophoretic material transport systems. For electrophoretic applications, the walls of interior channels of the electrokinetic transport system are optionally charged or uncharged. Typical electrokinetic transport systems are made of glass, charged polymers, and uncharged polymers. The interior channels are optionally coated with a material which alters the surface charge of the channel. A variety of electrokinetic controllers and systems are described, e.g., in Ramsey WO 96/04547, Parce et al. WO 98/46438 and Dubrow et al., WO 98/49548, as well as a variety of other references noted herein. Use of electrokinetic transport to control material movement in interconnected channel structures was described, e.g., in WO 96/04547 and US 5,858,195 to Ramsey. An exemplary controller is described in U.S. 5,800,690. Modulating voltages are concomitantly applied to the various reservoirs to affect a desired fluid flow characteristic, e.g., continuous or discontinuous (e.g., a regularly pulsed field causing the sample to oscillate direction of travel) flow of labeled components toward a waste reservoir. Particularly, modulation of the voltages applied at the various reservoirs can move and direct fluid flow through the interconnected channel structure of the device. Example System Figure 1A shows an example of a microfluidic device particularly suited to performing the target independent assays used to produce pre-screened libraries of the present invention. Target independent and/or target dependent assays that are fluorogenic assays, including protease assays, kinase assays, phosphatase assays, among many others are readily adapted for performance in the microfluidic device of Figure 1 A. Specifically, a chemical composition comprising a member (or members) of a master library is drawn from e.g., a master library array, e.g., a multiwell microtiter plate, through pipettor element 101, into main channel 102, where it contacts a continuous stream of enzyme flowed from reservoir 103, through side channel 104, into main channel 102. Once introduced into the main channel, the library member interacts with the flowing enzyme stream. The mixed enzyme/library members are flowed along main channel 102 past the intersection with channel 105. A continuous stream of fluorogenic (or other labeled) substrate which is contained in reservoir 106, is flowed along side channel 105 into main channel 102, whereupon it contacts and mixes with the continuous stream of enzyme/library member. Action of the enzyme upon the substrate produces an increasing level of the fluorescent signal. This increasing signal is indicated by the increasing fluorescence within the main channel as it approaches detection window 107. This increase in signal occurs in the absence of added library members, or in the presence of a library member with no effect on the enzyme/substrate interaction. Where a library member has an effect on the interaction of the enzyme and substrate, a variation appears in the signal produced. For example, assuming a fluorogenic substrate, a library member which inhibits the interaction of the enzyme with its substrate will result in less fluorescent product being produced. This will result in a non-fluorescent, or detectably less fluorescent region within the flowing stream as it passes detection window 107, which corresponds to the subject material region. After passage through the detection window, the flowing stream continues to waste well 108. A similar configuration is adapted by the addition of voltage channels 109 and 111 fluidly connected to independent sources of high/low voltage 110 and 112, illustrated in Figure IB. An alternative device particularly suited to assays, e.g., GST assays, of the present invention is illustrated in Figure 2. The microfluidic device includes main fluid channel 204 which runs longitudinally down the central portion of the body of the device. Main channel 204 originates in and is in fluid communication with buffer channel 206, and terminates, and is in fluid communication with waste reservoir 208. Buffer channel 206 is in fluid communication with buffer reservoirs 210 and 212. The device is shown having a number of channels intersecting the main channel 204. For example, buffer channel 214 terminates in, and is in fluid communication with main channel 204 near its originating point, and is, at its other terminus, in fluid communication with buffer reservoir 216. Sample introduction channel 218 also terminates in and is in fluid communication with main channel 204, and is, at its other terminus, in fluid communication with sample reservoir 220. Additional buffer/waste channels 222 and 224, and buffer/waste reservoirs 226 and 228 are also shown. The descriptors for the various wells and channels are primarily offered for puφoses of distinguishing the various channels and wells from each other. It will be appreciated that the various wells and channels can be used for a variety of different reagents depending upon the analysis to be performed. Sources Of Assay Components And Integration With Microfluidic Formats Sources of assay components such as cells or isolated proteins, sources of substrates or ligands, and sources of potential modulators, including members of the chemical composition libraries of the invention, can be fluidly coupled to the microchannels noted herein in any of a variety of ways. In particular, those systems comprising sources of materials set forth in Knapp et al. "Closed Loop Biochemical Analyzers" (WO 98/45481; PCTJUS98/06723) and Parce et al. "High Throughput Screening Assay Systems in Microscale Fluidic Devices" WO 98/00231 and, e.g., in 60/128,643 filed April 4, 1999, entitled "Manipulation of Microparticles In Microfluidic Systems," by Mehta et al. are applicable. In these systems, a "pipettor element" (i.e., a channel in which components can be moved from a source to a microscale element such as a second channel or reservoir) is temporarily or permanently coupled to a source of material. The source can be internal or external to a microfluidic device comprising the pipettor element, e.g., a "sipper chip" (basically, a microfluidic device which includes a microscale channel, such as a capillary, which is external to the main body of the microscale device). The device accesses external material sources such as microwell plates, membranes or other solid substrates comprising lyophilized components, bead matrices, wells or reservoirs in the body of the microscale device itself and others through the pipettor element. For example, the source of a cell type, assay component, or library member can be a microwell plate external to the body structure, having, e.g., at least one well with the selected cell type or reagent. Alternatively, a well disposed on the surface of the body structure comprising the selected cell type, component, or reagent, a reservoir disposed within the body structure comprising the selected cell type, component or reagent; a container external to the body structure comprising at least one compartment comprising the selected particle type or reagent, or a solid phase structure comprising the selected cell type or reagent in liquid, partially liquid, gel encapsulated, dried, partially dried, lyophilized or otherwise stabilized form. Chemical compositions comprising a library, substrates, targets, reagents and other assay components- are typically supplied to the microfluidic device in liquid form, e.g., in solution. Alternatively, chemical compositions, substrates, targets, reagents, and the like are provided attached to, or embedded in a particulate matrix such as a bead. The particulate matrix can be essentially any discrete, non-soluble material and in some cases, can be flowed through a microscale system. Example particles include beads and biological cells. For example, polymer beads (e.g., polystyrene, polypropylene, latex, nylon and many others), silica or silicon beads, ceramic beads, glass beads, magnetic beads, metallic beads and organic compound beads can be used. An enormous variety of particles are commercially available, e.g., those typically used for chromatography (see, e.g., the 1999 Sigma "Biochemicals and Reagents for Life Sciences Research" Catalog from Sigma (Saint Louis, MO), e.g., pp. 1921-2007; The 1999 Suppleco "Chromatography Products" Catalogue, and others), as well as those commonly used for affinity purification (e.g., Dynabeads™ from Dynal, as well as many derivitized beads, e.g., various derivitized Dynabeads™ (e.g., the various magnetic Dynabeads™, which commonly include coupled reagents) supplied e.g., by Promega, the Baxter Immunotherapy Group, and many other sources). Additional details regarding flow of particles are found in USSN 60/128,643 filed April 4, 1999, entitled "Manipulation of Microparticles In Microfluidic Systems," by Mehta et al. As noted herein, the definition for particles as intended herein includes both biological and non-biological particle material. Thus, cells are included within the definition of particles for puφoses of the present invention. Array particles can have essentially any shape, e.g., spherical, helical, spheroid, rod-shaped, cone-shaped, cubic, polyhedral or a combination thereof (of course they can also be irregular, as is the case for some cell-based particles). Cell based microfluidic assays are described in a variety of publications by the inventors and their co-workers, including, Parce et al. "High Throughput Screening Assay Systems in Microscale Fluidic Devices" WO 98/00231 and Knapp et al. "Closed Loop Biochemical Analyzers" (WO 98/45481; PCT/US98/06723). It is expected that one of skill is fully able to culture cells and introduce them into microfluidic systems. In addition to Parce et al. and Knapp et al., many references are available for the culture and production of many cells, including cells of bacterial, plant, animal (especially mammalian) and archebacterial origin. See e.g., Sambrook, Ausubel, and Berger (all supra), as well as Freshney (1994) Culture of Animal Cells, a Manual of Basic Technique, third edition Wiley- Liss, New York and the references cited therein, Humason (1979) Animal Tissue Techniques, fourth edition W.H. Freeman and Company; Ricciardelli, et al., (1989) In Vitro Cell Dev. Biol. 25:1016-1024; Payne et al. (1992) Plant Cell and Tissue Culture in Liquid Systems John Wiley & Sons, Inc. New York, NY (Payne); Gamborg and Phillips (eds) (1995) Plant Cell, Tissue and Organ Culture; Fundamental Methods Springer Lab Manual, Springer- Verlag (Berlin Heidelberg New York) (Gamborg); and Atlas and Parks (eds) The Handbook of Microbiological Media (1993) CRC Press, Boca Raton, FL (Atlas). Additional information for plant cell culture is found in available commercial literature such as the Life Science Research Cell Culture Catalogue (1998) from Sigma- Aldrich, Inc (St Louis, MO) (Sigma-LSRCCC) and, e.g., the Plant Culture Catalogue and supplement (1997) also from Sigma-Aldrich, Inc (St Louis, MO) (Sigma-PCCS). One particularly preferred use for cell-based microfluidic assays is to screen binding and/or internalization of cell ligands, e.g., cell receptor ligands, drugs, co- factors, etc. This screening is considerably facilitated by arraying different cell sets into arrays of cells, which can then have reagent trains comprising any factor to be tested for in vitro cellular activity flowed across the cell sets. Of course, cells can also be present in reagent trains and passed into contact with other array members. Cells optionally exist as sets of particles in a variety of formats in the present invention. For example, cells can be fixed to solid supports such as beads or other microparticles. Thus, arrays of the invention optionally include heterogeneous particles comprising solid supports and cells or other components of interest. In addition, as cells comprise surface proteins and other molecules, it is convenient to fix cell binding molecules (cell receptor ligands, cell wall binding molecules, antibodies, etc.) either to regions of the channels of the microfluidic device, or to particles which are then fixed or localized in position within the microfluidic device. A loading channel region is optionally fluidly coupled to a pipettor channel with a port external to the body structure. The loading channel can be coupled to an electropipettor channel with a port external to the body structure, a pressure -based pipettor channel with a port external to the body structure, a pipettor channel with a port internal to the body structure, an internal channel within the body structure fluidly coupled to a well on the surface of the body structure, an internal channel within the body structure fluidly coupled to a well within the body structure, or the like. As described more fully herein, the integrated microfluidic system of the invention can include a very wide variety of storage elements for storing reagents to be assessed. These include well plates, matrices, membranes and the like. The reagents are stored in liquids (e.g., in a well on a microtiter plate), or in lyophilized form (e.g., dried on a membrane or in a poious matrix such as a bead), and can be transported to an array component of the microfluidic device using conventional robotics, or using an electropipettor or pressure pipettor channel fluidly coupled to a reaction or reagent channel of the microfluidic system. In general, individual members of the library of chemical compositions are separately introduced into the assay systems described herein, or at least introduced in relatively manageable pools of library members. The relative effect of a library member (or pool of library members) on a particular biochemical system that is a target independent or target dependent assay is then assessed relative to a control system, which lacks an introduced library member. Increases or decreases in relative cellular, enzymatic, binding or other function are indicative that the library member is an enhancer or an inhibitor of the particular cellular or molecular function, respectively. DETECTORS AND INTEGRATED SYSTEMS Although the devices and systems specifically illustrated herein are generally described in terms of the performance of a few or one particular operation, it will be readily appreciated from this disclosure that the flexibility of these systems permits easy integration of additional operations into these devices. For example, the devices and systems described will optionally include structures, reagents and systems for performing virtually any number of operations both upstream and downstream from the operations specifically described herein. Such upstream operations include sample handling and preparation operations, e.g., cell separation, extraction, purification, culture, amplification, cellular activation, labeling reactions, dilution, aliquotting, and the like. Similarly, downstream operations may include similar operations, including, e.g., separation of sample components, labeling of components, assays and detection operations, electrokinetic or pressure-based injection of components into contact with cells or other assay components, or materials released from cells or produced by the reactions of the assays of the invention, or the like. In addition, the devices and systems optionally include structures for the storage of one or more master and/or pre-screened libraries, e.g., multiwell plates, pin arrays, bead arrays, etc. For example, the systems can include structures for cold storage, e.g., refrigeration or freezer units, storage of lyophilized materials, liquid storage, and the like. Upstream and downstream assay and detection operations include, without limitation, cell fluorescence assays, cell activity assays, molecular activity assays, receptor/ligand assays, immunoassays, and the like. Any of these elements can be fixed to array members, or fixed, e.g., to channel walls, or the like. The target independent assays of the invention, as well as any desired upstream or downstream operations are desirably performed in the context of an integrated system. An integrated system of the invention includes, for example, one or more multiwell plates, robotic elements (e.g., plate handling mechanisms, transport devices, etc.), controller, microfluidic device, detector, and a computer (e.g., including user input devices, data output devices, etc.). Instrumentation In general in the present invention, materials such as cells, fluorescently labeled substrates and/or products are optionally monitored and/or detected so that a function such as enzyme activity can be determined. Depending on the label signal measurements, decisions can be made regarding subsequent fluidic operations, e.g., whether to assay a particular modulator in detail to determine kinetic information. The integrated systems described herein generally include microfluidic devices, as described above, in conjunction with additional instrumentation for controlling fluid transport, flow rate and direction within the devices, detection instrumentation for detecting or sensing results of the operations performed by the system, processors, e.g., computers, for instructing the controlling instrumentation in accordance with preprogrammed instructions, receiving data from the detection instrumentation, and for analyzing, storing and inteφreting the data, and providing the data and inteφretations in a readily accessible reporting format. One example of an integrated system suitable for the performance of the target independent assays (and/or the target dependent assays) of the invention is the Labchip® microfluidic device high throughput screening system (HTS) by Caliper (Caliper Technologies Coφ., Mountain View, CA; www.calipertech.com.). The device includes, e.g., robotics, fluidics, plate handler, detector, etc. For the generation of common arrangements involving transfer of components to or from microtiter plates, a plate handling station is used. Several "off the shelf plate handling stations for performing such transfers are commercially available, including e.g., the Zymate systems from Zymark Coφoration (Zymark Center, Hopkinton, MA; http://www.zymark.com/) and other stations which utilize automatic pipettors, e.g., in conjunction with the robotics for plate movement (e.g., the ORCA® robot, which is used in a variety of laboratory systems available, e.g., from Beckman Coulter, Inc. (Fullerton, CA). In addition, a multicomponent system available from CCS Packard (www.carlcreative.com) incoφorates components for liquid handling, e.g., dispensing, pipetting and the like, transport and plate handling via its PlateTrak™, SideTrak®, and PlateStak™ elements. Controllers A variety of controlling instrumentation is optionally utilized in conjunction with the microfluidic devices described above, for controlling the transport and direction of fluids and/or materials within the devices of the present invention, e.g., by pressure-based or electrokinetic control. For example, in many cases, fluid transport and direction are controlled in whole or in part, using pressure based flow systems that incoφorate external or internal pressure sources to drive fluid flow. Internal sources include microfabricated pumps, e.g., diaphragm pumps, thermal pumps, Lamb wave pumps and the like that have been described in the art. See, e.g., U.S. Patent Nos. 5,271,724, 5,277,556, and 5,375,979 and Published PCT Application Nos. WO 94/05414 and WO 97/02357. As noted above, the systems described herein can also utilize electrokinetic material direction and transport systems. Preferably, external pressure sources are used, and applied to ports at channel termini. These applied pressures, or vacuums, generate pressure differentials across the lengths of channels to drive fluid flow through them. In the interconnected channel networks described herein, differential flow rates on volumes are optionally accomplished by applying different pressures or vacuums at multiple ports, or preferably, by applying a single vacuum at a common waste port and configuring the various channels with appropriate resistance to yield desired flow rates. Example systems are described, e.g., in USSN 09/238,467 filed 1/28/99. Typically, the controller systems are appropriately configured to receive or interface with a microfluidic device or system element as described herein. For example, the controller and/or detector, optionally includes a stage upon which the device of the invention is mounted to facilitate appropriate interfacing between the controller and/or detector and the device. Typically, the stage includes an appropriate mounting/alignment structural element, such as a nesting well, alignment pins and/or holes, asymmetric edge structures (to facilitate proper device alignment), and the like. Many such configurations are described in the references cited herein. The controlling instrumentation discussed above is also used to provide for electrokinetic injection or withdrawal of material downstream of the region of interest to control an upstream flow rate. The same instrumentation and techniques described above are also utilized to inject a fluid into a downstream port to function as a flow control element. Detector The devices herein optionally include signal detectors, e.g., which detect atomic mass, fluorescence, phosphorescence, radioactivity, pH, charge, absorbance, luminescence, temperature, magnetism or the like. Fluorescent detection is especially preferred and generally used for detection of many compounds (however, as noted, upstream and downstream operations can be performed on cells, assay components, library members or the like, which can involve other detection methods). In addition to fluorescence, evaporative light scattering and mass spectrometry are two additional detection mechanisms that are useful in the context of the present invention. The detector(s) optionally monitors one or a plurality of signals from downstream of an assay mixing point in which a labeled substrate and a cell or other assay component, are mixed with a library member. For example, the detector can monitor a plurality of optical signals which correspond to "real time" assay results. Example detectors include photo multiplier tubes, spectrophotometers, mass spectrometers, CCD arrays, a scanning detector, a microscope, a galvo-scann or the like. Cells, labels or other components which emit a detectable signal can be flowed past the detector, or, alternatively, the detector can move relative to the array to determine cell position (or, the detector can simultaneously monitor a number of spatial positions corresponding to channel regions, e.g., as in a CCD array). More specifically, the detectors used in the devices and systems of the present invention optionally include, e.g., one or more of: an optical detector, a microscope, a CCD array, a photomultiplier tube, a photodiode, an emission spectroscope, a fluorescence spectroscope, a phosphorescence spectroscope, a luminescence spectroscope, a spectrophotometer, a photometer, a nuclear magnetic resonance spectrometer, an electron paramagnetic resonance spectrometer, an electron spin resonance spectroscope, a turbidimeter, a nephelometer, a Raman spectroscope, a refractometer, an interferometer, an x-ray diffraction analyzer, an electron diffraction analyzer, a polarimeter, an optical rotary dispersion analyzer, a circular dichroism spectrometer, a potentiometer, a chronopotentiometer, a coulometer, an amperometer, a conductometer, a gravimeter, a mass spectrometer, a thermal gravimeter, a titrimeter, a differential scanning colorimeter, a radioactive activation analyzer, a radioactive isotopic dilution analyzer, and the like. Especially preferred detectors for use in the methods and devices of the invention include optical detectors and, e.g., electrospray ionization mass spectrometers, which can, e.g., be proximal to or coupled to one or more microscale channels of a device. Detector embodiments including mass spectrometer elements are discussed further below. The detector can include or be operably linked to a computer, e.g., which has software for converting detector signal information into assay result information (e.g., kinetic data of modulator activity), or the like. Signals are optionally calibrated, e.g., by calibrating the microfluidic system by monitoring a signal from a known source. A microfluidic system can also employ multiple different detection systems for monitoring the output of the system. Detection systems of the present invention are used to detect and monitor the materials in a particular channel region (or other reaction detection region). Once detected, the flow rate and velocity of cells in the channels is also optionally measured and controlled as described above. As described in PCTJUS98/11969, and 60/142,984, correction of kinetic information based upon flow velocity and other factors can be used to provide accurate kinetic information in flowing systems. As noted, examples of detection systems include optical sensors, temperature sensors, mass sensors, pressure sensors, pH sensors, conductivity sensors, and the like. Each of these types of sensors is readily incoφorated into the microfluidic systems described herein. In these systems, such detectors are placed either within or adjacent to the microfluidic device or one or more channels, chambers or conduits of the device, such that the detector is within sensory communication with the device, channel, or chamber. The phrase "within sensory communication" of a particular region or element, as used herein, generally refers to the placement of the detector in a position such that the detector is capable of detecting the property of the microfluidic device, a portion of the microfluidic device, or the contents of a portion of the microfluidic device, for which that detector was intended. For example, a pH sensor placed in sensory communication with a microscale channel is capable of determining the pH of a fluid disposed in that channel. Similarly, a temperature sensor placed in sensory communication with the body of a microfluidic device is capable of determining the temperature of the device itself. Particularly preferred detection systems include optical detection systems for detecting an optical property of a material within the channels and/or chambers of the microfluidic devices that are incoφorated into the microfluidic systems described herein. Such optical detection systems are typically placed adjacent to a microscale channel of a microfluidic device, and are in sensory communication with the channel via an optical detection window that is disposed across the channel or chamber of the device. Optical detection systems include systems that are capable of measuring the light emitted from material within the channel, the transmissivity or absorbance of the material, as well as the materials spectral characteristics. In preferred aspects, the detector measures an amount of light emitted from a material, such as a fluorescent or chemiluminescent material. As such, the detection system will typically include collection optics for gathering a light based signal transmitted through the detection window, and transmitting that signal to an appropriate light detector. Microscope objectives of varying power, field diameter, and focal length are readily utilized as at least a portion of this optical train. The light detectors are optionally spectrophotometers, photodiodes, avalanche photodiodes, photomultiplier tubes, diode arrays, or in some cases, imaging systems, such as charged coupled devices (CCDs) and the like. The detection system is typically coupled to a computer (described in greater detail below), via an analog to digital or digital to analog converter, for transmitting detected light data to the computer for analysis, storage and data manipulation. In the case of fluorescent materials such as labeled cells, labeled substrates and or labeled products, the detector typically includes a light source which produces light at an appropriate wavelength for activating the fluorescent material, as well as optics for directing the light source through the detection window to the material contained in the channel or chamber. The light source can be any number of light sources that provides an appropriate wavelength, including lasers, laser diodes and LEDs. Other light sources are used in other detection systems. For example, broad band light sources are typically used in light scattering/transmissivity detection schemes, and the like. Typically, light selection parameters are well known to those of skill in the art. As already noted, mass spectrometry provides another preferred method for detecting the results of target dependent or target independent screening assays. Mass spectrometry is a widely used analytical technique that can be used to provide information about, e.g., the isotopic ratios of atoms in samples, the structures of various molecules, including biologically important molecules, and the qualitative and quantitative composition of complex mixtures. Common mass spectrometer systems include a system inlet, an ion source, a mass analyzer, and a detector which are typically under vacuum. The detector is typically operably connected to a signal processor and a computer. Desoφtion ion sources for use in the present invention, include field desoφtion (FD), electrospray ionization (ESI), chemical ionization, matrix-assisted desoφtion/ionization (MALDI), plasma desoφtion (PD), fast atom bombardment (FAB), secondary ion mass spectrometry (SIMS), and thermospray ionization (TS). ESI sources are especially preferred. Mass spectrometry is well-known in the art. References specifically addressing the interfacing of mass spectrometers with microfluidic devices include, e.g., Karger, et al., U.S. Pat. No. 5,571,398, "PRECISE CAPILLARY ELECTROPHORETIC INTERFACE FOR SAMPLE COLLECTION OR ANALYSIS" and Karger, et al. U.S. Pat. No. 5,872,010 "MICROSCALE FLUID HANDLING SYSTEM." General sources of information about mass spectrometry include, e.g., Skoog, et al. Principles of Instrumental Analysis (5 th Ed.) Hardcourt Brace & Company, Orlando (1998). In general, mass spectrometers are well suited to interface with microfluidic devices, because the usual input into a microfluidic system is a capillary channel. In the present invention, this mass spectrometry capillary is simply fluidly coupled to channel in the microscale system. Methods of affixing external capillaries to microscale systems include various bonding and/or drilling operations, e.g., as described, e.g., in Parce, et al., U.S. Pat. No. 5,972,187 "ELECTROPIPETTOR AND COMPENSATION MEANS FOR ELECTROPHORETIC BIAS." One advantage of coupling mass spectrometers to microfluidic systems is that the ionization chamber of a mass spectrometer is usually under vacuum. This vacuum can be used as a negative pressure source for the microfluidic system, providing a driving mechanism for the system. Another advantage is that labels are not typically required for detection of anayltes. A number of specific microfluidic device configurations which are specifically adapted to screening by mass spectrometry are described in "MICROSCALE ASSAYS AND MICROFLUIDIC DEVICES FOR TRANSPORTER, GRADIENT INDUCED, AND BINDING ACTIVITIES" by Parce et al., USSN 60/176,093, filed January 14, 2000. In addition to the many microfluidic systems noted herein, other automated approaches can also be practiced with the target independent assays, libraries and methods of the invention. For example, the FLIPR (Fluorescence Imaging Plate Reader) was developed to perform quantitative optical screening for cell based kinetic assays (Schroder and Neagle (1996) "FLIPR: A New Instrument for Accurate, High Throughput Optical Screening" Journal of Biomolecular Screening l(2):75-80). This device can be adapted to the present invention, e.g., by using the assays of the invention in the indicated methods. In general, the detector can exist as a separate unit, but can also be integrated with the controller system, into a single instrument. Integration of these functions into a single unit facilitates connection of these instruments with the computer (described below), by permitting the use of few or a single communication port(s) for transmitting information between the controller, the detector and the computer. Computer As noted above, either or both of the controller system and/or the detection system are coupled to an appropriately programmed processor or computer which functions to instruct the operation of these instruments in accordance with preprogrammed or user input instructions, receive data and information from these instruments, and inteφret, manipulate and report this information to the user. As such, the computer is typically appropriately coupled to one or both of these instruments (e.g., including an analog to digital or digital to analog converter as needed). The computer typically includes appropriate software for receiving user instructions, either in the form of user input into a set parameter fields, e.g., in a GUI, or in the form of preprogrammed instructions, e.g., preprogrammed for a variety of different specific operations. The software then converts these instructions to appropriate language for instructing the operation of the fluid direction and transport controller to carry out the desired operation. The computer then receives the data from the one or more sensors/detectors included within the system, and inteφrets the data, either provides it in a user understood format, or uses that data to initiate further controller instructions, in accordance with the programming, e.g., such as in monitoring and control of flow rates, temperatures, applied voltages, and the like. In the present invention, the computer typically includes software for the monitoring of materials in the channels. Additionally, the software is optionally used to control electrokinetic or pressure modulated injection or withdrawal of material. The injection or withdrawal is used to modulate the flow rate as described above, to mix components, and the like. Multi-module workstations In some embodiments, the target independent and/or target dependent assays of the invention are performed in an integrated system including a multi-module workstation. The multi-module workstations of the invention typically include one or more microfluidic device, as well as optionally including one or more devices for performing high-throughput assays directly in microtiter plates, e.g., plate handlers such as the ORCA™ and PlateTrak™ described above, plate readers, or from pin or bead arrays. Screening modules comprising microfluidic or other microscale devices, multiwell plate readers, (e.g., fluorimetric, photometric, colorimetric plate readers such as the Elx800 from Bio-Tek Instruments, Inc: www.copalis.com; and the Ultramark and Benchmark Plate readers from Bio-Rad: www.bio-rad.com ), and/or devices for the automated, e.g., robotic, performance of target independent (and/or target dependent) assays, or any combination thereof, are arranged to provide access to the individual modules by a robotic mechanism. Each module, which can be operated singly, or in conjunction with one or more additional module in the multi-module workstation, includes the necessary means and components for carrying out a specified target independent or target dependent assay, or a subportion thereof (e.g., sample preparation, incubation, etc.), as described in further detail above. The robotic mechanism can include an armature, conveyor belt, or other transport mechanism for obtaining and manipulating one or more assay component or library array, e.g., a chemical composition library arrayed in a stack of multiwell plates. The armature or other transport mechanism can be movably deployed between modules of the multi-module workstation (or the modules can be movably deployed), and conveys one or more assay component, including but not limited to library arrays, reagents, cells, substrates, etc., to the individual modules (or, alternately, the modules can be moved to the library members, or both components can be moved to achieve operable coupling of the module and the library). The armature or other transport mechanism can be transported between modules (or vice-versa) by a mechanism such as a track, a cable and pulley, a conveyor belt, rollers, robotic means or the like, e.g., positioned proximal to or between one or more screening modules, or between a screening module and one or more assay components. Figure 9 illustrates an exemplary configuration of such a workstation. Substrates comprising a master library array, e.g., in one or more multiwell plates, are arranged in an ordered manner in plate storage module 1012 (optionally including, e.g., refrigeration element, freezer element, or the like). The user selects assay parameters via user input element 1015 (e.g., a keyboard, touch screen, mouse, or the like) which conveys an instruction set through controller element 1013 (e.g., a P.C. computer, drive mechanism, etc.) to track robot 1010. Selected substrates are retrieved by robotic armature 1011 from plate storage module 1012 and transported by track robot 1010 to one of assay modules 1001 through 1008. These assay modules will typically have the appropriate assay device elements (e.g., microfluidic chips and detection elements) for performing the relevant assay. Upon completion of a first target independent assay, the substrate is optionally transported to a second assay module for evaluation in an additional target independent or target dependent assay. Results of one or more of the target independent and/or target dependent assays are displayed on output device 1014 (although depicted as a single output device, multiple output elements can be used in the system, e.g., each coupled to one or more of the assay modules). Controller element 1013 optionally includes storage media for storing databases corresponding to the libraries of interest. The storage media can also be in separate elements such as computers or disk drives. Ordinarily, the storage media is operably coupled to the assay modules to store the results of the assays. Databases which include the positions of assayed components and information for which assays the assayed components show desirable activity can also be included in controller element 1013 or in separate computers or other coupled data storage systems. In this embodiment, and in certain alternate embodiments, multiple pre- screening target independent assays and/or target dependent screening assays can be performed at each of the assay modules. Similarly, a single assay module running multiple target independent assays and/or target dependent screening assays can be used instead of multiple assay modules to achieve similar results. Databases One aspect of the present invention includes entering descriptors for members of a library of pre-screened compositions into a database. These descriptors can include any relevant information which describes any physical, logical or spatial characteristic or activity of any of the members of the pre-screened composition library (or any of the other libraries noted herein). In general, the database is embodied in a computer or computer readable medium for access by a user and/or integrated system, e.g., which acts on the library based upon information in the database (e.g., physically manipulates one or more element of the integrated system, e.g., plates, microfluidic components or the like in response to the information in the database). Standard desktop applications such as word processing software (e.g., Microsoft Word™ or Corel WordPerfect™), database software (e.g., spreadsheet software such as Microsoft Excel™, Corel Quattro Pro™, or database programs such as Microsoft Access™ or Paradox™) can be adapted to the present invention by inputting a character string corresponding to the descriptor to be entered into the database. For example, the computer system embodying the database can include the foregoing software having the appropriate character string information, e.g., used in conjunction with a user interface (e.g., a GUI in a standard operating system such as a Windows, Macintosh or LINUX system) to manipulate strings of characters. Systems for analysis in the present invention can include a digital computer with software for tracking library entries, assay results, or the like and for using that information to manipulate the system (e.g., to select appropriately active members identified m pre-screening target independent assay steps or in target dependent assay screening steps The computer can be, e.g., a PC (Intel x86 or Pentium chip- compatible computer, running any available operating system, e.g., DOS™, OS2™ WINDOWS™ WINDOWS NT™, WINDOWS95™, WINDOWS98™, LINUX, Apple OS, Power PC, UNIX) or other commercially common computer which is known to one of skill. Software for manipulating information descπptor elements is available, or can easily be constructed by one of skill using a standard programming language such as Visualbasic, Fortran, Basic, Java, or the like. Assay Kits The present invention also provides kits for producing the braπes of the invention. In particular, these kits typically include microfluidic devices, systems, modules and workstations for performing the assays of the invention. A kit optionally contains additional components for the assembly and/or operation of a multimodule workstation of the invention including, but not restπcted to robotic elements (e g., a track robot, a robotic armature, or the like), plate handling devices, fluid handling devices, and computers (including e.g., input devices, monitors, cp u., and the like). Generally, the microfluidic devices descπbed herein are optionally packaged to include reagents for performing the device's preferred function. For example, the kits optionally include any of microfluidic devices descπbed along with assay components, e.g., buffers, reagents, enzymes, serum proteins, receptors, etc., for performing the target independent assays used to produce the pre-screened hbraπes of the invention. In the case of prepackaged reagents, the kits optionally include pre-measured or pre-dosed reagents that are ready to incoφorate into the assay methods without measurement, e.g., pre-measured fluid aliquots, or pre-weighed or pre-measured solid reagents that may be easily reconstituted by the end-user of the kit Such kits also typically include appropπate instructions for using the devices and reagents, and in cases where reagents are not predisposed in the devices themselves, with appropπate instructions for introducing the reagents into the channels and/or chambers of the device. In this latter case, these k ts optionally include special ancillary devices for introducing mateπals into the microfluidic systems, e g., appropπately configured syπnges/pumps, or the like (in one preferred embodiment, the device itself compπses a pipettor element, such as an electropipettor for introducing mateπal into channels and chambers within the device) In the former case, such kits typically include a microfluidic device with necessary reagents predisposed in the channels/chambers of the device. Generally, such reagents are provided in a stabilized form, so as to prevent degradation or other loss during prolonged storage, e.g., from leakage. A number of stabilizing processes are widely used for reagents that are to be stored, such as the inclusion of chemical stabilizers (i.e., enzymatic inhibitors, microcides/bacteriostats, anticoagulants), the physical stabilization of the material, e.g., through immobilization on a solid support, entrapment in a matrix (i.e., a bead, a gel, etc.), lyophilization, or the like. The elements of the kits of the present invention are typically packaged together in a single package or set of related packages. The package optionally includes written instructions for carrying out one or more target independent assay in accordance with the methods described herein. Kits also optionally include packaging materials or containers for holding microfluidic device, system or reagent elements. EXAMPLES The following examples of target independent assays performed in a microfluidic device are provided by way of illustration and not by way of limitation. One of skill will recognize a variety of parameters which can be changed while still achieving substantially similar results. Any one or more of the following assays can be performed simultaneously or sequentially to provide the pre-screened libraries of the present invention. EXAMPLE 1: HSA ASSAY Human serum albumin (HSA) is the most abundant protein in blood, and is bound by a wide variety of biological materials. Many drugs bind HSA reversibly and with high affinity. In drug discovery, the determination of drug binding to HSA is used to prioritize potential leads obtained from a target screening before proceeding to animal and/or clinical trials. In the present invention, large libraries of chemical compounds are first evaluated for binding to HSA, to provide pre-screened libraries that are then evaluated in one or more target dependent, or screening assay. The HSA assay protocol was adapted from published fluorogenic approaches to detect compounds interacting with human serum albumin in buffer (e.g., Epps et al. (1995) Analytical Biochemistry 227:342). In brief, this assay is a competitive binding assay that measures displacement of a dye binding to HSA by a library member. Two major sites on albumin have been determined to be important for the binding of both dyes and potential drugs. In the present example, two different dyes were used that bind selectively to each of the major binding sites on albumin (Site I and II), respectively: dansyl- 1-sulfonamide (DNSA) and dansyl sarcosine (DS). These dyes possess the property of greatly increased quantum yield or fluorescence upon binding to albumin. A compound that binds to albumin through one of these two sites displaces the dye and result in a fluorescence decrease which is optionally used to calculate the Kd or rank order of binding to albumin. Assays were run with only one dye at a time, but the dyes are spectrally compatible and could be run simultaneously. The albumin-dye concentrations can be chosen to yield predetermined Kd values, and can be about ~ 4 μM or better; corresponding drug concentrations are then on the order of 20 μM. The HSA assays were performed in a microfluidic device of the design illustrated in Figure 1 A, and previously described herein. The buffer system is phosphate- buffered saline (PBS) at pH 7.4, and typical assay conditions require times of 10-60 sec/compound and compound amounts of less than 0.1 pmol/measurement at one compound concentration. De-fatted and essentially globulin-free human serum albumin was used for the assay. The assay is as follows: K d e albumin + dye — albumin - dye K dru albumin + drug — > albumin - drug In this example, only the site I dye (DNSA) is used. The albumin concentration is 15 μM and the dye is the site I specific dye, DNSA at 30 μM. The experiments were run at room temperature. The fluorescence excitation is centered at 330 nm and the emission is at 475-525 nm. The pressure applied to achieve flow was approximately 32 inches of water. The duration of experiments ranged from 10 to 60 minutes. The instrument used to collect the data is shown in Figure 1A. In these experiments, albumin and DNSA were pre-mixed in the PBS buffer described above and added to wells 103 and 106 on the microfluidic device illustrated in Fig. 1A. (The albumin and dye can also be fed in separately to the main pipettor channel, dye from well 103, albumin from well 106). The inhibitor in the HSA-drug binding plot (Figure 3A) is phenylbutazone, a drug known to bind to site I on HSA. The drug concentrations are ~ 7, 17, 35, 55, 75, 110, 150, and 180 μM. The assay cycle time for each sample is 25 seconds. The % inhibition values in the inhibition vs phenylbutazone plot (Figure 3B) were extracted from data shown in Figure 3A (where two repetitions are shown). The assay was run for ~ 45 minutes repeating the same titration (8 different inhibitor concentrations) for 10 repetitions. In the HSA-binding to six drugs plot (Figure 3C), the different drugs are at 175 μM in 1% DMSO/PBS buffer. The cycle time was 30 seconds/sample and the microfluidic device (Figure 1) used was coated with a PEG (polyethylene glycol) coating. The six different drugs used were: phenylbutazone, sulfinpyrazone, acetylsalicylic acid, tolbudamide, warfarin and ibuprofen. There were two different types of negative control that had no drug in them, one is PBS buffer and one was l-%DMSO/PBS buffer. In the rank order of drug binding to HSA plot, the ranking for microfluidic device and cuvette were performed and compared with literature values. Experimental concentrations and buffers for the cuvette experiment were essentially similar to those described above for the microfluidic device experiments. These results are as follows: Rank Order of Drug binding to HSA (Strongest to Weakest) Chip Cuvette Literature phenylbutazone phenylbutazone phenylbutazone sulfinpyrazone sulfinpyrazone sulfinpyrazone tolbudamide warfarin tolbudamide acetylsalicylic acid= tolbudamide warfarin warfarin = ibuprofen acetylsalicylic acid acetylsalicylic acid ibuprofen ibuprofen In the features of HSA binding assay compilation, the consumption was based on experimental conditions given above and within the range of concentrations given. The cycle time was the current, non-optimized cycle time. The percent DMSO that could be tolerated by the assay was tested in a cuvette format. Rank order of drug binding is maintained up to ~ 5% DMSO. The following is a compilation of the features of HSA binding assay: FEATURES OF HSA BINDING ASSAY Concentrations Human Serum albumin and dyes: 5-50 μM Compound: 10-500μM Consumption Assay Reagents 50-500 femtomoles/datapoint; 10μl/8 hrs. Compound 10-500 femtomoles/datapoint; lnl / sample Time Cycle time 25 sec; 145 datapoints/ hr. Percent DMSO in Assay 0.1 to 5% EXAMPLE 2: GST ASSAY Glutathione-s-transferase (GST) plays a significant role in antioxidant defense and is part of the biochemical adaptation of animals to environmental stress. GST catalyzes the conjugation of reduced glutathione to a wide variety of endogenous and exogenous lipid-soluble xenobiotics, including dimethylaniline analogs, aminopyrine, imipramine, chloφromazine, and related antidepressants, and pesticides (Figure 4A). As depicted, (1.) indicates the structure of Glutathione (γ-Glu-Cys-Gly), while (2.) indicates the general scheme of reactions catalyzed by GST on an electrophillic substrate. In the present invention, GST assays are utilized to obtain pre-screened libraries with desirable characteristics with respect to GST activity. It will be appreciated that a desirable level of GST activity varies with the intended application of the compounds being evaluated. GST Assays were performed in 100 mM bisTRIS at pH 6.5, 1M NDSB (non-detergent sulfobetaine), 5 mM NaCl using pentafluorobenzoyl fluorescein (pFBF) at 10-20 μM (available from Molecular Probes). GST (rat liver) was purchased from Sigma Chemicals (St Louis, MO). The assay was performed in a planar microfluidic device having the channel layout illustrated in Figure 2. Figure 4, panel B illustrates the structure of example substrates for performing the GST assay, as well as the results of the assay (panel C). As depicted in Figure 4B, (1.) is a colorimetric substrate (2,4-dinitro- chlorobenzene); (2.) is a fluorescent substrate (a coumarin derivative), and (3.) is a fluorescein derivative. Figure 4C shows data for the fluorescein derivative in the planar chip experiment, in lOOmM Bis-Tris, pH 6.5, 1M NDSB, 5mM NaCl. EXAMPLE 3: PROTEASE ASSAYS Pre-screened libraries which have been evaluated for their effects, e.g., as inhibitors or activators, on cellular proteases are a feature of the invention. "Proteases" are enzymes that degrade proteins by hydrolyzing peptide bonds between amino acid residues. They are also known as proteinases. Categories of proteases include thiol proteases, acid proteases, serine proteases, and the like. Example proteases include, but are not limited to, carboxypeptidase A, subtilisin, papain, and pepsin. Protease assays are described in greater detail in, e.g., U.S. Patent Application No. 09/093,542, filed June 8, 1998, which is incoφorated herein by reference. To perform a protease assay, a substrate, e.g., a protein, is mixed with or otherwise contacted by a protease. A variety of fluorogenic protease substrates are commercially available, including, e.g., p-nitrophenolic compounds, and the like. The protease catalyzes a reaction with the substrate, thus forming products, such as protease cleavage products. In the present invention, protease assays are utilized to evaluate chemical compositions for their ability to modulate, e.g., inhibit or activate, the protease. In the present invention a protease inhibition assay is performed in a continuous-flow format in the microscale channels of a microfluidic device. Typically, the reactants move through the channels due to the application of pressure or electrokinetic forces as described above. When two reactants are introduced into the same channel, the two reactants mix and contact each other to react and form products. For example, a protease is optionally flowed through a microfluidic channel under pressure. The protease is then contacted by or mixed with a substrate, e.g., a protein, peptide or the like. Substrates are typically labeled, e.g., fluorogenic substrates. A protease catalyzes the hydrolysis of a substrate producing degraded protein products, e.g., cleaved protein fragments. Various characteristics of protease reactions are studied using protease assays, e.g., enzyme mechanisms, kinetics, inhibition and the like. A protease inhibition assay provides, e.g., information on the types of compounds that inhibit proteases and the level of inhibition they provide. For example, pepstatin acts as a protease inhibitor by inhibiting the activity of carboxyl proteases. The present invention provides high throughput assay systems suitable for testing many compositions in protease inhibition assays in a short amount of time. The chemical compositions of the master library are optionally added before, during, or after the enzyme and substrate are contacted, depending on the format of the assay. For example, to perform a protease inhibition assay, a library member is introduced into the microscale channel in which the protease reaction is carried out. The reaction proceeds in the presence of the potential modulator. A potential modulator compound is optionally drawn from a microtiter plate containing a plurality of samples. The plurality of samples optionally comprises potential modulators, inhibitors, and/or activators. An example of results obtained in an exemplary protease inhibition assay trials are shown in Figure 5. Assay parameters, enzyme consumption and substrate consumption statistics for protease assays performed in a standard multiwell plate format and in a microfluidic device (LabChip® device) are compared in Table 1. A 125-fold reduction in enzyme consumption accompanied by a 6,700-fold reduction in substrate consumption is obtained in the microfluidic device as compared to a multiwell plate format. In addition, as significant increase in throughput is achieved with over 4,000 assays being performed per 12 hour period. TABLE 1. PROTEASE ASSAYS EXAMPLE 4: KINASE ASSAYS Protein kinases catalyze the phosphorylation of proteins by transferring the γ- phosphate group from ATP onto the hydroxy group of a serine, threonine, or tyrosine residue of a target peptide or protein. It has been estimated that as many as 2-3% of all genes in eukaryotic organisms encode protein kinases (Cobb et al. (1991) Cell Regul 2:965). While many of these are potential targets for drug development in the treatment of a wide variety of diseases, including cancer, as a group, they are the subject of important target independent assays. Kinase assays are generally described in U.S. Patent Application No. 60/108,628, incoφorated herein by reference. Kinase activity has traditionally been assayed using radioactive ATP and following the transfer of the isotopically labeled phosphate from ATP to a peptide or protein substrate. A typical kinase assay of the present invention, however, involves the use of a fluorescently tagged peptide, e.g., "KEMPtide." Phosphorylation is detected as a shift in the mobility of labeled KEMPtide. For example: Tag-Leu- Arg-Arg-Ala-Ser-Leu-Gly ("Kemptide;" net charge:q) Φ Protein Kinase A, ATP, cAMP Tag-Leu-Arg-Arg-Ala-Ser(OPO 3 2-\ )-Leu-Gly (Phosphorylated "Kemptide;" net charge:q "2 ) Figure 6A schematically illustrates the kinase mobility shift assay. As depicted, binding results in a change in the mobility of bound species, resulting in a change in detectable signal. Assay results in the presence of varying levels of inhibiting compounds are illustrated in Figures 6B-E, including the calculation of kinetic constants (Figure 6C). As depicted, Figure 6B shows an ATP Titration and detection by mobility shift for a protein kinase A assay. The buffer conditions were lOOmM HEPES, pH7.5, 5mM MgCl 2 , 1M NDSB-195, 10 mM DTT, 0.01% Triton. Figure 6C shows a lineweaver- Burk plot and ATP titration for a protein kinase A assay (■ ;♦; representing two series of assays). 6D shows results of a protein kinase A assay with lOμM H-9 inhibitor injections. The buffer conditions were 100 mM HEPES pH 7.5, 5 mM MgCl 2 , 1 M NDSB-195, 10 mM DTT, 0.01% Triton X-100, 0.05mM ATP, lOμM Fl-Kemptide substrate + 140 nM PKA catalytic subunit. 6E shows the results of a Protein Kinase A assay performed in a "sipper chip" (a chip with an external capillary for sampling fluid from sources external to the chip, such as a microtiter dish). The results show titration of an inhibition, with detection by mobility shift. The buffer conditions were 100 mM HEPES pH 7.5, 5 mM MgCl 2 , 1 M NDSB-195, 10 mM DTT, 0.01% Triton X-100, 0.05mM ATP, 100 nM PKA catalytic subunit 10 μM Fl-Kemptide substrate. EXAMPLE 5: PHOSPHATASE ASSAYS Similarly, enzymes that catalyze the dephosphorylation of a peptide or protein are also the subject of target independent assays used to provide the pre-screened libraries of the invention. In brief, the phosphatase assay utilizes a fluorogenic substrate dFMU (6,8-difluoro-4-methylumbeliferyl phosphate), which produces a fluorescent signal upon dephosphorylation (e.g., upon incubation with a phosphate). The reaction is described in detail in Kopf-Sill et al., U.S Patent Application No. 09/093,542 filed June 8, 1998. Phosphatase reactions were performed in 1M NDSB-195 in 50 mM HEPES, pH7.9. Reagent concentrations were 125 nM LAR and 50μM dFMUP. The system was programmed to run a series of controls followed by the enzyme plus substrate, optionally including a known inhibitor. The total current flux remained constant in the main reaction channel with the proportion of overall flux from each reagent and buffer well being selected to provide the desired final reagent concentration in the main reaction channel. The fluorescence response was monitored in each step. Figure 7A shows typical data obtained from a phosphatase assay (a substrate titration) performed in a microfluidic device. Raw data for the K m , V max , k cat and Ki are plotted in Figure 7B. The results of a least squares fit of the results for no inhibitor, 35 μM and 69μM inhibitor were calculated (Figure 7C) and compared to the results of phosphatase reactions performed in a cuvette with a spectrophotometer (Table 2). TABLE 2. PHOSPHATASE ASSAYS EXAMPLE 5: G-PROTEIN COUPLED RECEPTOR- CELL BASED ASSAYS Pre-screened libraries of the invention are also produced by evaluating large master libraries in cell based assays. For example, G-Protein coupled receptor assays are a target independent assay of the present invention. G-Protein coupled receptor assays typically measure calcium flux across a cell membrane using a labeled calcium indicator, as illustrated schematically in Figure 8A. In the current example, WT3-CHO cells were obtained from ATCC and cultured in RPMI 1640 containing 10% FBS, 10 mM HEPES, Pen/Strep, 1 mM Sodium Pyruvate and 2 mM L-Glutamate, 100 μg/ml G418. The cells (10 x 106 cells/5 ml) were then loaded with Fluo-3 (Molecular Probes Inc., Eugene, OR) by incubation with 4 μM Fluo-3-AM in Hank's balanced salt solution (HBSS) containing 1 mg/ml BSA, 20 mM HEPES, 0.04% pluronic acid, 2.5 mM probenecid for 40 min at 37° C. The cells were counterstained with 1 μM Syto-62 (Molecular Probes Inc.) for 15 min at room temperature after Fluo-3 loading. The dye loaded cells were washed twice by resuspending the pelleted cells in HBSS containing HEPES and 1 mg/ml BSA. The cells were resuspended in Cell Analysis Buffer consisting of the same wash medium with the addition of a density agent, Hypaque (Pharmacia Biotech)or Optiprep (Nycomed), added to match the density of the cells and 8% (w/v) Ficoll-400 (Fluka) to adjust the buffer viscosity to 4.5 centipoise. The G-Protein coupled receptor assay was performed in a microfluidic device (Figure 8B) with a pipettor element 801, etched with 90 μm wide by 20 μm deep channels and are configured as shown in Figure 8B. The design of the microfluidic device is such that the given viscosity of buffers, the sample in HBSS + HEPES is diluted 1/3 with buffer + cells, and the agonist from the agonist well 802 is diluted 1/5 with the cell-sample mixture. The channels were filled with cell analysis buffer and the wells were filled with 18 μl of assay medium. Waste well 804 was connected to a vacuum source set at 0.8 lbs/sq. inch to start the flow of buffer to this empty well. Cells were added into the cell well 806, and cells flowing through the main channel 803 were interrogated by the epifluoresence detector 805 down-stream of the agonist addition point. The flow rate after agonist addition was 0.8 mm sec and the detector was set at a position that allowed an incubation time of 20 sec after agonist addition prior to detection. Samples were drawn from 96 well microplates at 30 second intervals. The data stream was collected at 20 hertz in a Agilent 2100 Bioanalyzer using Caliper LabChip® Technology. Fluo-3 emission was collected at 520 nm using a green filter and Syto-62 emission was collected at 680 nm using a red filter: a blue LED at 488 nm excitation wavelength was used for both dyes. A software filter was used to segregate the fluorescent emission readings collected when cells were in the reading area of the detector. The ratio of the Fluo-3/Syto-62 cell readings were averaged during the 30 sec sampling period after background subtraction. Fluorescein dye injections were used to mark the start and end of groups of 20 sample injections. The data are illustrated in Figures 8C-8F. EXAMPLE 6: CYTOCHROME P450 ASSAY Cytochrome P450 assays are important tools for assessing the metabolic and potentially toxic effects of a drug lead. Human cytochrome P450 preparations are available commercially from companies such as Gentest Coφoration. These enzymes carry out metabolic oxidation of chemical compounds. There are a number of fluorogenic substrates available for monitoring P450 activity, e.g., the coumarin-derivatives, resorufin-derivative or fluorescein-derivatives obtainable from Molecular Probes. The availability of fluorogenic substrates for monitoring the activity of these enzymes means that these assays can be carried out in a continuous-flow microfluidic device-based assay format. The following are examples of available fluorogenic substrates useful, e.g., for p450 assays: (1.) Coumarin Derivatives, e.g., 3-cyano-7-ethoxycoumarin-->3-cyano-7-hydroxycoumarin (Ex/Em max: 408/ 450 nm; extinct, coeff: 43,000); (2.) Resorufin derivatives, e.g., phenoxazone"^resorufin (Ex/Em max: 571/ 585 nm; extinct, coeff: 54,000); (3.) Flourescein derivatives, e.g., fluorescein diethyl ether ■ ^fluoresecein (Ex/Em max: 490/ 520 nm; extinct, coeff: 70,000). Kinetic parameters for four different Human P450 isozyme and substrate combinations were taken from the Gentest website (Table 3). Using these enzyme reaction parameters and the known flow parameters for the microfluidic device design of Figure 1 A, it is possible to calculate the product formation rate and the total amount of product formed for given starting concentrations of enzyme and substrate (Table 4). The ratio of the amount of product formed to the estimated concentration detection limit for these molecules provides an indication of the feasibility of running a continuous-flow assay. For the present calculation, the enzyme concentration, was assumed to be the maximum obtainable using the Gentest P450 preparations and the known dilution factor for a microfluidic device design of Figure 1 A, using a 30 second sampling time. The final substrate concentrations were set near their K m values, and a detection limit of 50 μM was assumed for the fluorogenic reaction products. The calculations indicate that all four of these enzyme- catalyzed reactions can be observed in the microfluidic design, in spite of the very slow turnover kinetics exhibited by these enzymes. The percent inhibition expected to be observed for a hypothetical inhibitor was also calculated using the same set of assay parameters to ensure than under these conditions the assay is sensitive to inhibition. TABLE 3. CYTOCHROME P450: KINETIC PARAMETERS 1 Apparent K m from Gentest Coφoration technical bulletin 2 Apparent k cat (37 °C) from Gentest Coφoration technical bulletin 3 Assumed value 4 Assumed minimum detectable concentration The net consumption of reagents in the microfluidic device format was calculated from the assumed reaction conditions and compared to that calculated for the microplate assay protocol listed on the Gentest website (Table 5). In this example, running the assay in the microfluidic device format yields a 280-fold reduction in enzyme consumption and a 16,500-fold reduction in substrate consumption, with an estimated throughput of approximately 2000 assay per 12 hour day. TABLE 5. COMPARISON OF CYTOCHROME P450 ASSAYS IN MICROPLATE AND MICROFLUIDIC DEVICE FORMATS. All publications, patents, patent applications, internet web pages and other documents are herein incoφorated by reference for all puφoses as if each individual publication, patent, patent application, internet web page or other document was specifically and individually indicated to be incoφorated by reference for all puφoses. Although the present invention has been described in some detail by way of illustration and example for puφoses of clarity and understanding, it will be apparent that certain changes and modifications may be practiced within the scope of the appended claims.

Claims: WHAT IS CLAIMED IS: 1. A method of generating a pre-screened chemical composition library, the method comprising: pre-screening a large master library of compositions in at least one target independent assay, thereby providing a library of pre-screened compositions. 2. The method of claim 1, wherein the pre-screening step comprises physically separating members of the master library to produce the library of pre-screened compositions. 3. The method of claim 2, wherein the members of the master library are separated based upon a positive or negative activity in the pre-screening step. 4. The method of claim 1, further comprising entering descriptors for members of the library of pre-screened compositions into a database, which database is embodied in a computer or computer readable medium. 5. A database embodied in a computer or computer readable medium made by the method of claim 4. 6. The method of claim 7, further comprising screening the master library, the library of pre-screened compositions, or the second library of pre-screened compositions, in at least one additional target independent assay. 7. The method of claim 1, further comprising screening the master library, or the library of pre-screened compositions, in at least one additional target independent assay, thereby producing a second library of pre-screened compositions. 8. The method of claim 7, further comprising entering descriptors for members of the second library of pre-screened compositions into a database, which database is embodied in a computer or computer readable medium. 9. A database embodied in a computer or computer readable medium made by the method of claim 8. 10. The method of claim 1, wherein the large master library is made by synthesizing one or more members of the master library. 11. The method of claim 1, wherein the library of pre-screened compositions comprises at least about 1000 or more compositions. 12. The method of claim 11, wherein the library of pre-screened compositions comprises at least about 10,000 or more compositions. 13. The method of claim 12, wherein the library of pre-screened compositions comprises at least about 100,000 or more compositions. 14. The method of claim 13, wherein the library of pre-screened compositions comprises at least about 1,000,000 or more compositions. 15. The method of claim 1, wherein the target independent assay evaluates an effect correlated to one or more target independent parameters selected from: serum half- life, cellular uptake, oral availability, cellular or organismal viability, cellular or organismal toxicity, apoptosis, cellular adhesion modulation, target independent receptor modulation, target independent enzyme activity modulation, target independent protein activity modulation, target independent nucleic acid activity modulation, glucuronide conjugation modulation, sulfate conjugation modulation, amino acid conjugation modulation, acylation modulation, methylation modulation, transcription modulation, translation modulation, protein folding modulation, modulation of cell growth, membrane permeability, membrane integrity, metabolic stability, thermal stability, solubility, solution viscosity, solution turbidity, acidity, basicity, RedOx state, superoxide secretion, lipid peroxidation, octanol/water partition, precipitation in one or more buffers. 16. The method of claim 15, wherein the target independent assay is performed by flow cytometry in a cell-focusing device. 17. The method of claim 16, wherein the flow cytometry distinguishes between live cells and dead cells. 18. The method of claim 17, wherein the flow cytometry detects the fluorescence of a dye or dye-conjugate, which dye or dye conjugate is selected from the group consisting of: calcein AM, BCECF AM, ethidium bromide, propidium iodide, a cationic dye, a cationic membrane permeable dye, a neutral dye, a membrane permeable neutral dye, an anionic dye, an anionic membrane permeable dye. 19. The method of claim 15, wherein the target independent assay evaluates the effect of the selected composition on calcium flux across a cell membrane, which cell membrane is a component of a cell, which cell is preloaded with a fluorescent calcium indicator. 20. The method of claim 15, wherein the target independent assay evaluates the binding of a selected composition on a serum protein. 21. The method of claim 20, wherein the serum protein is Human Serum Albumin (HSA). 22. The method of claim 21, wherein the target independent assay evaluates the ability of a selected composition to inhibit binding of the HSA by at least one fluorescent dye, which fluorescent dye is selected from among dansyl- 1-sulfonamide (DNSA) or dansyl sarcosine (DS). 23. The method of claim 22, wherein the HSA is present at a concentration of about 15 μM; or wherein a concentration of HSA and a concentration of the dye are chosen to give a Kd of approximately 4 μM. 24. The method of claim 15, wherein the target independent assay evaluates inhibition of an enzyme, which enzyme is selected from among: a glutathione-s-transferase, a protease, a peptidase, a kinase, a phosphatase, a G protein, an ATPase, a cytochrome P450, a ligase, a carboxylesterase, an epoxide hydrolase, an aza- or nitro-reductase, a carbonyl reductase, a disulfide reductase, a sulfoxide reductase, a quinone reductase, an alcohol dehydrogenase, an aldehyde dehydrogenase, an aldehyde oxidase, a xanthine oxidase, a monoamine or diamine oxidase, a prostaglandin sythase, a flavin- monooxygenase, and a dehalogenase. 25. The method of claim 24, wherein the enzyme is a glutathione-s- transferase, and wherein the target independent assay evaluates the ability of the selected composition to inhibit the conversion of a substrate to a product by the glutathione-s- transferase. 26. The method of claim 25, wherein the substrate is a fluorogenic or a colorigenic substrate of glutathione-s-transferase, which fluorogenic or colorigenic assay is 2,4-dinitro-chlorobenzene, a coumarin derivative, or a fluorescein derivative. 27. The method of claim 26, wherein the substrate is pentafluorobenzoyl fluorescein (pFBF), which pFBF is present at a concentration of about 10-20 μM. 28. The method of claim 24, wherein the enzyme is a protease, and wherein the target independent assay evaluates the effect of the selected composition on a fluorescent signal resulting from a cleavage of a fluorogenic substrate by the protease. 29. The method of claim 28, wherein the fluorogenic substrate is AMC. 30. The method of claim 24, wherein the enzyme is a kinase, and wherein the target independent assay evaluates the effect of the selected composition on a mobility shift induced by the kinase on a substrate. 31. The method of claim 30, wherein the substrate is a fluorescently tagged peptide. 32. The method of claim 31 , wherein the fluorescently tagged peptide comprises the sequence: Tag-Leu-Arg-Arg-Ala-Ser-Leu-Gly. 33. The method of claim 24, wherein the enzyme is a phosphatase, and wherein the target independent assay evaluates the effect of the selected composition on a fluorescent signal resulting from dephosphorylation of a fluorogenic substrate by the phosphatase. 34. The method of claim 33, wherein the fluorogenic substrate is dFMU. 35. The method of claim 24, wherein the enzyme is a cytochrome P450, and wherein the target independent assay evaluates the effect of the selected composition on a fluorescent signal generated by conversion of a fluorogenic substrate by the cytochrome P450. 36. The method of claim 35, wherein the substrate is a coumarin derivative, a resofugin derivative or a fluorescein derivative. 37. The method of claim 24, wherein the enzyme is a G-protein, and wherein the target independent assay evaluates the effect of the selected composition on a fluorescent signal generated by an action of a G-protein. 38. The method of claim 37, wherein the fluorescent signal is generated by a calcium flux coupled to a G-protein. 39. The method of claim 38, wherein the calcium flux is across a cell membrane, which membrane comprises a receptor-G-protein complex. 40. The method of claim 39, wherein the cell membrane is a component of a cell, which cell is preloaded with a fluorescent calcium indicator. 41. The method of claim 1, comprising performing the target independent assay in a microfluidic device. 42. The method of claim 41, wherein the microfluidic device comprises one or more pippetor channel. 43. The method of claim 41, wherein the master library is arrayed in one or more multi-well plate, on one or more solid substrate, or in one or more bead matrix, thereby producing a master library array. 44. The method of claim 43, wherein the multi-well plates comprise one or more of: 96 well plates, 384 well plates and 1536 well plates; or wherein the solid substrate comprises one or more of: a membrane having a plurality of members of the array fixed on the membrane; or wherin the bead matrix comprises one or more microfluidic bead arrays. 45. The method of claim 43, further comprising compiling a data set, which data set correlates results of the at least one target independent assay with one or more members of the master library array. 46. The method of claim 45, wherein the data set correlates results of a plurality of target independent assays to a plurality of members of the master library array. 47. The method of claim 43, further comprising performing at least one additional target independent assay to produce one or more additional pre-screened libraries. 48. The method of claim 46, wherein the first and one or more additional diverse pre-screened libraries are arrayed in the same one or more multi-well plates, or on the same one or more solid substates or in the same one or more bead matrix. 49. The method of claim 46, comprising performing the target independent assays in a multi-module workstation which comprises more than one modules which perform different target independent assays. 50. The method of claim 1, further comprising assaying at least one composition identified in the pre-screening step in a target dependent assay. 51. The pre-screened library of claim 1. 52. The pre-screened library of claim 51, wherein the pre-screened library comprises in excess of approximately 100 compositions. 53. The pre-screened library of claim 51 , wherein the pre-screened library comprises in excess of approximately 1,000 compositions. 54. The pre-screened library of claim 51, wherein the pre-screened library comprises in excess of approximately 10,000 compositions. 55. The pre-screened library of claim 51, , wherein the pre-screened library comprises in excess of approximately 100,000 compositions. 56. The pre-screened library of claim 51 , wherein the pre-screened library comprises in excess of approximately 1,000,000 compositions. 57. The pre-screened library of claim 51, wherein the library comprises members which have a desired activity in more than one target independent assay. 58. The pre-screened library of claim 57, wherein the pre-screened library is substantially devoid of members which have a negative effect in a plurality of target independent assays. 59. The pre-screened library of claim 57, wherein the pre-screened library is represented by a data set, which data set correlates results of one or more target independent assay with well locations in the master library array. 60. The pre-screened library of claim 59, wherein the data set is stored in a computer readable medium. 61. A multi-module workstation for performing multiple target independent assays, the work station comprising: a plurality of screening modules structurally configured to perform target independent assays; at least one substrate comprising a plurality of chemical compositions; a robotic mechanism in proximity to and functionally connecting the plurality of screening modules to the at least one substrate, which robotic mechanism, during operation of the multi-module workstation, moves the at least one substrate to a position proximal to or within at least one of the plurality of screening modules; and, a computer assisted robotic control system operably linked to the robotic mechanism, which control system controls movement of the at least one substrates by the robotic mechanism. 62. The multi-module workstation of claim 61, wherein the robotic mechanism, or a second robotic mechanism, during operation of the device, positions one or more of the screening modules, or a portion thereof proximal to the one or more substrates. 63. A multi-module workstation for performing multiple target independent assays, the work station comprising: a plurality of screening modules structurally configured to perform target independent assays; at least one substrate comprising a plurality of chemical compositions; a robotic mechanism in proximity to at least one of the plurality of screening modules, which robotic mechanism positions the at least one of the plurality of screening modules proximal to or within the one or more substrate; and, a computer assisted robot control system operably linked to the robotic mechanism, which robot control system controls movement of the at least one of the plurality of screening modules by the robotic mechanism. 64. The multi-module workstation of claim 63, wherein the robotic mechanism, or a second robotic mechanism, during operation of the device, positions one or more of the at least one substrates, or a portion thereof, proximal to one or more of the plurality of screening modules. 65. The workstation of claim 61 or 63, wherein the screening modules comprise at least one microfluidic device. 66. The workstation of claim 65, wherein the at least one microfluidic device comprises at least one pipettor channel. 67. The workstation of claim 61 or 63, wherein at least one of the plurality of the target independent screening modules are configured to perform an assay which evaluates an effect correlated to one or more target independent parameters selected from: serum half-life, cellular uptake, oral availability, cellular or organismal viability, cellular or organismal toxicity, apoptosis, cellular adhesion, target independent receptor binding or modulation, target independent enzyme activity modulation, target independent protein activity modulation, target independent nucleic acid activity modulation, glucuronide conjugation modulation, sulfate conjugation modulation, amino acid conjugation modulation, acylation modulation, methylation modulation, transcription modulation, translation modulation, protein folding modulation, modulation of cell growth, membrane permeability, membrane integrity, metabolic stability, thermal stability, solubility, solution viscosity, solution turbidity, acidity, basicity, RedOx state, superoxide secretion, lipid peroxidation, octanol/water partition, precipitation in one or more buffers. 68. The workstation of claim 61 or 63, wherein at least one of the plurality of the target independent screening modules are configured to perform an assay selected from: a flow cytometry assay, an assay which evaluates the effect of a selected composition on a biochemical system, an assay which measures a calcium flux across a cell membrane, an assay which evaluates binding of a serum protein, an assay which evaluates binding to Human Serum Albumin, and an assay which evaluates the effect of a selected composition on an enzyme. 69. The workstation of claim 61 or 63, wherein the at least one substrate is selected from one or more of: a solid substrate; a bead array and a multiwell plate. 70. The workstation of claim 61 or 63, wherein the robotic mechanism comprises one or more of: a conveyor belt positioned between at least two of the plurality of target independent screening modules, a slide mechanism positioned between at least two of the plurality of target independent screening modules, rollers positioned between at least two of the plurality of target independent screening modules, a cable and pulley mechanism positioned between at least two of the plurality of target independent screening modules, a robotic armature positioned proximal to one or more of the target independent screening modules, and a robotic armature positioned proximal to one or more of the substrates. 71. The workstation of claim 61 or 63, wherein the computer assisted robot control system comprises one or more component selected from: (A) one or more instruction sets for: movement of one or more substrates by the robotic mechanism between at least two of the plurality of screening modules, positioning of substrates by the robotic mechanism in or proximal to least two of the plurality of screening modules, movement of at least one of the plurality of screening modules into contact with at least one of the one or more substrates, or selection of library members; (B) one or more data set coπelating results of one or more target independent assay with one or more members of the master library array; and, (C) a user interface for programming inputs into the robot control system, which inputs selectively control the robotic mechanism.

Inventors: CHOW CALVIN Y H, HODGE C NICHOLAS, KNAPP MICHAEL R, KOPF-SILL ANNE R, NIKIFOROV THEO T, PARCE J WALLACE, CHOW, CALVIN, Y., H., HODGE, C., NICHOLAS, KNAPP, MICHAEL, R., KOPF-SILL, ANNE, R., NIKIFOROV, THEO, T., PARCE, J., WALLACE
Applicants: CALIPER TECHN CORP, CHOW CALVIN Y H, HODGE C NICHOLAS, KNAPP MICHAEL R, KOPF SILL ANNE R, NIKIFOROV THEO T, PARCE J WALLACE, CALIPER TECHNOLOGIES CORP., CHOW, CALVIN, Y., H., HODGE, C., NICHOLAS, KNAPP, MICHAEL, R., KOPF-SILL, ANNE, R., NIKIFOROV, THEO, T., PARCE, J., WALLACE
Application year: 2000
Main classification: G01N33
IPC codes: C07B61, C12M1, C12Q1, C40B60, G01N33, G01N37