Structure-Based Drug Design of Peptide Mimetics Containing Large P3 Moieties as Inhibitors of Factor VIIa
Peptide mimetic compounds 9d and 9h showed good selectivity for FVIIa/TF over other serine proteases. Xray crystal structure analysis revealed that a large moiety at P3 interacted in a novel manner with the 170-loop and was accompanied by ligand-induced conformational change of the 170-loop. From additional optimization, we discovered compound 10b, an excellent extrinsic pathway-selective inhibitor.
Keywords: Structure-based drug design, Serine protease, FVIIa inhibitor, 2 x APTT/2 x PT ratio, X-ray crystal structure, Ligand-induced conformational change
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