Computer based screening of compound databases: 1. Preselection of benzamidine-based thrombin inhibitors.
We present a computational protocol which uses the known three-dimensional structure of a target enzyme to identify possible ligands from databases of compounds with low molecular weight. This is accomplished by first mapping the essential interactions in the binding site with the program GRID. The resulting regions of favorable interaction between target and ligand are translated into a database query, and with UNITY a flexible 3D database search is performed. The feasibility of this approach is calibrated with thrombin as the target. Our results show that the resulting hit lists are enriched with thrombin inhibitors compared to the total database.
Fox
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Boehringer Ingelheim Pharma KG, Department of Chemical Research/Structural Research, Biberach an der Riss, Germany. thomas.fox@bc.boehringer-ingelheim.com
Haaksma
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D001550:Benzamidines / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D017076:Computer-Aided Design; D016208:Databases, Factual; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D008958:Models, Molecular; D013917:Thrombin / Q000037:antagonists & inhibitors* / Q000737:chemistry
D001550:Benzamidines; D004791:Enzyme Inhibitors; D013917:Thrombin