The primary purpose of the Core B facility is to provide researchers of the P01 with rapid and cost effectivehigh throughput screening and molecular modeling of their targets with the ultimate goal of identifying 'hits'for further chemical lead optimization and biological characterization. The Core B facility comprises twofunctional units: Experimental HTS and Virtual HTS/ Molecular Modeling. The two units work closely togetherto provide complementary approaches toward screening biomolecular targets and toward aiding the leadoptimization process by serving as a resource for molecular modeling studies. The specific functions of CoreB include: 1) Experimental HTS: To screen the chemical libraries prepared by projects 1, 2, 3, 4 and 5 aswell as in-house chemical libraries to identify compounds capable of inhibiting SHP2 and chymotrypsin-likeproteasome activities as well as Rb/Raf, Bcl-xL/Bax and MDM2/MDMX/p53 associations. Our in-housechemical libraries include the publicly available NCI Diversity, Natural Product, Challenge and MechanisticSets as well as a 20,000 diverse chemical compound library we purchased from Chemical Diversity Labs(ChemDiv). The 20,000 compounds were selected from ChemDiv's ~600,000 compound collection, whichconsists of ChemDiv's internal synthesis efforts as well as procurement from laboratories around the world ,to represent maximal chemical and structural diversity. Experimental assays will also be preformed for theevaluation of ADME properties. 2) Virtual HTS: To search compound databases (-650,000 3D models)based on the X-ray or NMR structures of SHP2, MDM2, Bcl-xL and the chymotrypsin-like subunit of theproteasome. 3) Molecular Modeling: The best scoring compounds from virtual screening and, in particularthe experimentally confirmed 'hits' from virtual screening, will be subjected to additional molecular modelingstudies including 3D QSAR analysis to aid the lead optimization process. 4) Prediction of ADME Properties:The QikProp computer program (Schrodinger, L.L.C.) will be employed for the in silica prediction of ADMEproperties of 'hits' and to optimize ADME properties of potential drug candidates. 5) Data analysis andmanagement: To facilitate communication among projects 1, 2, 3, 4 and 5 and Core A, B and C, we have setup a centralized database for all related scientific data, The maintenance of the infra-structure of thedatabase is supported by the Moffitt IT Core Facility. Core B will be responsible for the management of thecontent of the databases. The database will allow users a) to register and track all compounds prepared byprojects 1,2,3,4 and 5 from synthesis/acquiring, shipment to testing; b) to search and review chemical andbiological data from projects 1, 2, 3, 4, 5 and Core B and C.
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