Combinatorial docking and combinatorial chemistry: design of potent non-peptide thrombin inhibitors
H J Böhm1, D W Banner, L Weber
1Hoffmann-La Roche Ltd, Pharmaceuticals Division, Basel, Switzerland.
Abstract:
A computational algorithm was used to design automatically novel thrombin inhibitors that are available from a single-step chemical reaction. The compounds do not contain amide bonds, are achiral and have a molecular weight below 400. Of the 10 compounds that were synthesized, five bind to thrombin with a Ki in the nanomolar range. Subsequent X-ray structure determination of the thrombin-inhibitor complex for the best compound (Ki = 95 nM) confirms the predicted binding mode. The novel algorithm is applicable to a broad range of chemical reactions.
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