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Letters in Drug Design & Discovery

Author(s): Kunihiro Hattori, Toshiro Kozono, Haruhiko Sato, Masateru Ohta, Keiko Esaki, Takehisa Kitazawa, Kazutaka Yoshihashi, Akihisa Sakamoto, Yoshiaki Watanabe, Takuya Shiraishi, Takaki Koga, Tohru Esaki, Hitoshi Iikura, Yoshiyuki Ono, Hirofumi Kodama, Masayuki Haramura and Shojiro Kadono

DOI: 10.2174/157018009787582606

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Structure-Based Drug Design of Peptide Mimetics Containing Large P3 Moieties as Inhibitors of Factor VIIa

Page: [86 - 92] Pages: 7

  • * (Excluding Mailing and Handling)

Abstract

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