1V3X

Factor Xa in complex with the inhibitor 1-[6-methyl-4,5,6,7-tetrahydrothiazolo(5,4-c)pyridin-2-yl] carbonyl-2-carbamoyl-4-(6-chloronaphth-2-ylsulphonyl)piperazine

1V3X の概要

• エントリーDOI: 10.2210/pdb1v3x/pdb
• 関連するPDBエントリー: 1fax 1xka
• 分子名称: Coagulation factor X, HEAVY CHAIN, Coagulation factor X, LIGHT CHAIN, CALCIUM ION, ... (5 entities in total)
• 機能のキーワード: glycoprotein, hydrolase, serine protease, plasma, blood coagulation factor, protein inhibitor complex, calcium-binding
• 由来する生物種: Homo sapiens (human); 詳細
• 細胞内の位置: Secreted: P00742 P00742
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 32549.44

構造登録者

Suzuki, M. (登録日: 2003-11-07, 公開日: 2004-11-07, 最終更新日: 2024-11-20)

主引用文献

Haginoya, N.,Kobayashi, S.,Komoriya, S.,Yoshino, T.,Suzuki, M.,Shimada, T.,Watanabe, K.,Hirokawa, Y.,Furugori, T.,Nagahara, T.
Synthesis and conformational analysis of a non-amidine factor Xa inhibitor that incorporates 5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine as S4 binding element
J.Med.Chem., 47:5167-5182, 2004

PubMed Abstract: Our exploratory study was based on the concept that a non-amidine factor Xa (fXa) inhibitor is suitable for an orally available anticoagulant. We synthesized and evaluated a series of N-(6-chloronaphthalen-2-yl)sulfonylpiperazine derivatives incorporating various fused-bicyclic rings containing an aliphatic amine expected to be S4 binding element. Among this series, 5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine type 61 displayed orally potent anti-fXa activity and evident prolongation of prothrombin time (PT) with the moderate bioavailability in rats. The X-ray crystal analysis afforded an obvious binding mode that 5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine and 6-chloronaphthalene respectively bound to S4 and S1 subsites. In this X-ray study, we discovered a novel intramolecular S-O close contact. Ab initio energy calculations of model compounds deduced that conformers with the most close S-O proximity were most stable. The Mulliken population analysis proposed that this energy profile was caused by both of electrostatic S-O affinity and N-O repulsion. The results of these calculations and X-ray analysis suggested a possibility that the restricted conformation effected the affinity to S4 subsite of fXa.

PubMed: 15456260
DOI: 10.1021/jm049884d

実験手法

X-RAY DIFFRACTION (2.2 Å)