The new Drug Discovery Core at MUSC provides a mechanism for faculty, postdocs and students to discover chemical agents that affect targets that they hypothesize to be involved in human diseases. The Drug Discovery Core provides the following resources: expertise for assay development; chemical libraries; instrumentation for high-throughput screening, including robotic liquid-handling and state-of-the-art cell imaging, and technical support for screening. The compounds can then be used as biochemical probes of the functions of the target proteins, and/or developed into new therapeutic agents. This provides opportunities for new research funding, patents and technology commercialization.
Assay development assistance: Assay development is a key step in the discovery process. In many cases, the Investigator will have established an assay for their target and the Drug Discovery Core (DDC) will adapt this assay to a screening mode. If no assay is yet available, it will be developed in collaboration with the Investigator. To maximize assay throughput, we prefer homogenous assays that are conducted in microtiter plates and followed by quantification of an absorbance, fluorescence or luminescence signal. Use of the InCell Analyzer 1000 allows rapid imaging within 96-well microtiter plates, so that the subcellular distribution of fluorescent proteins or probes can be determined.
Compounds: A critical consideration in any drug discovery program is the source of compounds to be tested for biological activity. The screening library used by the DDC at MUSC consists primarily of 50,000 compounds from the DIVERSet collection from the ChemBridge Corporation. DIVERSet is a unique subset of drug-like, hand-synthesized small molecules, rationally selected to form a "universal" library that covers the maximum pharmacophore diversity with the minimum number of compounds. It is geared for primary screening against a wide range of biological targets, including those where no structural information is available. The entire ChemBridge collection contains nearly 500,000 compounds, providing a rich source for structure-activity studies.
Screening: All of the actual screening is conducted by technicians within the DDC. Investigators are kept aware of the status of the screening effort and are regularly updated on hits, allowing immediate translation of the screening effort into a molecular pharmacology effort. The throughput of this effort is dependent on the particular assay.
Computational chemistry: As sufficient data becomes available from the screen, hits are compiled and structurally analyzed. Similar compounds within the screening library are identified through substructure searching to allow rapid identification of chemotypes with activity against the target. The DDC utilizes computational modeling to derive Quantitative Structure-Activity Relationships for each target studied. If the 3-dimensional structure of the target is known, virtual screening can be used to rapidly select compounds for testing. Also, docking analyses provide important information about how compounds interact with the target, and so can facilitate the design of new analogs
The Drug Discovery Core maintains multifunctional Molecular Devices Spectramax M5 and PerkinElmer Envision microplate readers that are capable of quantifying absorbance, luminescence, fluorescence intensity, time-resolved fluorescence and fluorescence polarization. These are robotically coupled to a Caliper SciClone 3000 ALH automated liquid-handling workstation and a Molecular Devices AquaMax microplate washer. A GE InCell Analyzer 1000 with liquid handling and the OptiGrid Structure Light Module is used for cell imaging-based assays.
