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COMPUTATIONAL STRUCTURAL PROTEOMICS AND RATIONAL DRUG DESIGN RUBEN ABAGYAN Department of Molecular Biology The Scripps Research Institute Founder, Molsoft, LLC ABSTRACT: Large-scale discovery of new human genes, gene families and isozymes creates an exciting biomedical opportunity. The sequence-structure gap is rapidly increasing despite the efforts of the companies and centers for high-throughput structural proteomics. However, advanced modeling by homology techniques can be employed to generate 3D models for most of the interesting new gene family members. This opens many new opportunities for structural structure based functional annotation and molecular design. First, we have developed two new techniques to assist rational drug design using crystallographic structures or models by homology. The binding pockets can be automatically identified even if the native ligand is unknown. This algorithm has been tested on over 10,000 complexes. We have also built a comprehensive database of protein pockets and clustered them into families. Second, a deformed ligand binding pocket in a model by homology can be refined by explicit global optimization of one or several known ligands and surrounding receptor side-chains. Third, a procedure is described to identify a native ligand from a collection of all known biological substrates. The procedure was also applied to some receptors including GPCRs. Finally, new computational technology for virtual ligand screening allows us to generate alternative receptor conformations and perform flexible docking of hundreds of thousands of virtual compounds to the binding site. The success of this technology is demonstrated on several benchmarks and in six experimental projects, which tested the prediction results. For well-defined binding pockets only about 1% of the initial compound set actually needs to be synthesized and tested. Using ICM docking and scoring technology we have identified new ligands in a number of cases, including cases in which a model was used instead of a crystallographic structure and a case in which proteinprotein interaction has been targeted. Some of the recent results tested experimentally include: the de novo design of novel antagonists of thyroid hormone receptor, for which no antagonists were known before and, consequently, no antagonist-bound structure was known; de novo design of ligands targeting Ephrin-Ephrin receptor interactions. Friday, September 20, 2002 11:00 a.m. – 1:00 p.m. (Talk starts at 11:15) Building 4, Room 231 Professor Abagyan's invitation is possible because of the generous support of Genome Therapeutics Corporation, with special thanks to Dr. Keith Weinstock. Massachusetts Institute of Technology Department of Mathematics Cambridge, MA 02139