1TA2

Crystal structure of thrombin in complex with compound 1

1TA2 の概要

• エントリーDOI: 10.2210/pdb1ta2/pdb
• 関連するPDBエントリー: 1SL3 1TA6
• 分子名称: thrombin, Hirudin, 1-(2-AMINO-3,3-DIPHENYL-PROPIONYL)-PYRROLIDINE-3-CARBOXYLIC ACID 2,5-DICHLORO-BENZYLAMIDE, ... (4 entities in total)
• 機能のキーワード: thrombin inhibitor complex, blood clotting, hydrolase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• 由来する生物種: Homo sapiens (human); 詳細
• 細胞内の位置: Secreted, extracellular space: P00734; Secreted: P28504
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 34952.83

構造登録者

Tucker, T.J.,Brady, S.F.,Lumma, W.C.,Lewis, S.D.,Gardel, S.J.,Naylor-Olsen, A.M.,Yan, Y.,Sisko, J.T.,Stauffer, K.J.,Lucas, B.Y.,Lynch, J.J.,Cook, J.J.,Stranieri, M.T.,Holahan, M.A.,Lyle, E.A.,Baskin, E.P.,Chen, I.-W.,Dancheck, K.B.,Krueger, J.A.,Cooper, C.M.,Vacca, J.P. (登録日: 2004-05-19, 公開日: 2004-06-08, 最終更新日: 2024-11-20)

主引用文献

Tucker, T.J.,Brady, S.F.,Lumma, W.C.,Lewis, S.D.,Gardel, S.J.,Naylor-Olsen, A.M.,Yan, Y.,Sisko, J.T.,Stauffer, K.J.,Lucas, B.Y.,Lynch, J.J.,Cook, J.J.,Stranieri, M.T.,Holahan, M.A.,Lyle, E.A.,Baskin, E.P.,Chen, I.-W.,Dancheck, K.B.,Krueger, J.A.,Cooper, C.M.,Vacca, J.P.
Design and synthesis of a series of potent and orally bioavailable noncovalent thrombin inhibitors that utilize nonbasic groups in the P1 position
J.Med.Chem., 41:3210-3219, 1998

PubMed Abstract: As part of an ongoing effort to prepare therapeutically useful orally active thrombin inhibitors, we have synthesized a series of compounds that utilize nonbasic groups in the P1 position. The work is based on our previously reported lead structure, compound 1, which was discovered via a resin-based approach to varying P1. By minimizing the size and lipophilicity of the P3 group and by incorporating hydrogen-bonding groups on the N-terminus or on the 2-position of the P1 aromatic ring, we have prepared a number of derivatives in this series that exhibit subnanomolar enzyme potency combined with good in vivo antithrombotic and bioavailability profiles. The oxyacetic amide compound 14b exhibited the best overall profile of in vitro and in vivo activity, and crystallographic studies indicate a unique mode of binding in the thrombin active site.

PubMed: 9703466
DOI: 10.1021/jm9801713

実験手法

X-RAY DIFFRACTION (2.3 Å)