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Ronald J. Perez
Graduate Program of Cellular and Molecular Pharmacology
Thesis Advisor: William J. Welsh, PhD
RWJMS Research Tower
Friday, May 1, 2009
Drug discovery is a highly resource consuming and lengthy process. In the past decade, drug discovery has moved toward more rational approaches due to the increase in computational capability and a better understanding of protein-ligand interactions. The combinations of available structural data with millions of drug-like compounds paint a promising picture for the application of structure-and ligand-based drug design approaches. Further, application of virtual screening to large chemical databases allows for rapid identification of a limited number of promising candidates for drug design. In this context, we have applied a systematic virtual screening approach named Hybrid Structure Based method to identify molecular lead antagonists for integrins alpha IIb beta 3 and alpha 5 beta 1 alpha IIb beta 3 is a well known target of medicinal agents used to treat acute coronary syndrome. Among the small molecules tested for their ability to inhibit the binding of biotinylated fibrinogen to immobilized alpha IIb beta 3, three had IC50 values of 27 microM, 164 microM, and 291 microM. Whereas our active control, GRGDSP, had an IC50 value of 8 microM. In addition, more recently integrin alpha 5 beta 1 has attracted much interest as a target of angiogenesis. Our attempt to apply this systematic screening approach to identify antagonists yielded two compounds with IC50 values of 66 microM and 124 microM.