High Throughput Screening and Molecular Modeling

点击翻译按钮获取中文摘要

The primary purpose of the Core B facility is to provide researchers of the NCDDG with rapid and cost effective high throughput screening, molecular modeling, and as a future direction, X-ray crystallography of their targets with the ultimate goal of identifying "hits' for further chemical lead optimization and biological characterization. The Core B facility comprises two functional units: Experimental HTS and Virtual HTS & Molecular Modeling. The two units work closely together to provide complementary approaches toward screening molecular targets. The specific functions of Core B include: (1) Experimental HTS: To design, develop and employ biochemical assays formatted for HTS. To screen the combinatorial chemical libraries prepared by program 1 as well as publicly available chemical libraries, such as NCI Diversity and Natural Product Sets, in order to identify compounds capable of inhibiting the catalytic activities of geranylgeranyltransferase I (GGTase I), Rho guanine nucleotide exchange factors (RhoGEFs) and Rho kinase (ROCK). (2) Virtual HTS: To computationally dock libraries of small molecules from compound databases (>700,000 3D structures) onto defined surfaces of existing crystal structures in order to identify compounds that modulate the catalytic activities of GGTase I and RhoGEFs. (3) Molecular Modeling: The best scoring compounds from virtual screening and, in particular the experimentally confirmed "hits" from virtual screening, as well as those from experimental HTS will be subjected to additional molecular modeling studies. (4) In Silica Prediction of ADME Properties: The QikProp program (Schrodinger, L.L.C.) will be employed to predict ADME properties of "hits" and to optimize ADME properties of potential drug candidates. Data analysis and management: To facilitate communication among programs 1, 2 and 3 and Core A and B, we have set up a centralized database for all related scientific data. The maintenance of the infra-structure of the database is supported by the Moffitt Bioinformatics Services and Research IT (BRIT). Core B will be responsible for the management of the content. The database will allow users a) to register and track all compounds from synthesis/acquiring, shipment to testing; b) to search and review chemical and biological data from Programs 1,2, 3 and Core B.