Combinatorial docking and combinatorial chemistry: Design of potent non-peptide thrombin inhibitors

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.