Crystallographic analysis of potent and selective factor Xa inhibitors complexed to bovine trypsin

被引：36

作者：

Whitlow, M ^{[1
]}

Arnaiz, DO ^{[1
]}

Buckman, BO ^{[1
]}

Davey, DD ^{[1
]}

Griedel, B ^{[1
]}

Guilford, WJ ^{[1
]}

Koovakkat, SK ^{[1
]}

Liang, A ^{[1
]}

Mohan, R ^{[1
]}

Phillips, GB ^{[1
]}

Seto, M ^{[1
]}

Shaw, KJ ^{[1
]}

Xu, W ^{[1
]}

Zhao, ZC ^{[1
]}

Light, DR ^{[1
]}

Morrissey, MM ^{[1
]}

机构：

[1] Berlex Biosci, Richmond, CA 94804 USA

来源：

ACTA CRYSTALLOGRAPHICA SECTION D-STRUCTURAL BIOLOGY | 1999年 / 55卷

关键词：

D O I：

10.1107/S0907444999007350

中图分类号：

Q5 [生物化学];

学科分类号：

071010 ; 081704 ;

摘要：

Factor Xa is a serine protease which activates thrombin (factor IIa) and plays a key regulatory role in the blood-coagulation cascade. Factor Xa is, therefore, an important target for the design of anti-thrombotics. Both factor Xa and thrombin share sequence and structural homology with trypsin. As part of a factor Xa inhibitor-design program, a number of factor Xa inhibitors were crystallographically studied complexed to bovine trypsin. The structures of one diaryl benzimidazole, one diaryl carbazole and three diaryloxypyridines are described. All five compounds bind to trypsin in an extended conformation, with an amidinoaryl group in the S1 pocket and a second basic/hydrophobic moiety bound in the S4 pocket. These binding modes all bear a resemblance to the reported binding mode of DX-9055a in bovine trypsin and human factor Xa.

引用

页码：1395 / 1404

页数：10

共 32 条

[1] NEW LEAST-SQUARES REFINEMENT TECHNIQUE BASED ON FAST FOURIER-TRANSFORM ALGORITHM [J].