Crystallographic analysis of potent and selective factor Xa inhibitors complexed to bovine trypsin
| Autor: | Sunil K. Koovakkat, William J. Guilford, Wei Xu, Brad O. Buckman, Marian Seto, Brain Griedel, David R. Light, Morrissey Michael M, David D. Davey, Kenneth J. Shaw, Damain O. Arnaiz, Amy Liang, Gary Phillips, Zuchun Zhao, Raju Mohan, Marc Whitlow |
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| Rok vydání: | 1999 |
| Předmět: |
Models
Molecular Benzimidazole medicine.drug_mechanism_of_action Macromolecular Substances Protein Conformation Stereochemistry Factor Xa Inhibitor Molecular Conformation Plasma protein binding In Vitro Techniques Crystallography X-Ray chemistry.chemical_compound Thrombin Protein structure Structural Biology Hydrolase Electrochemistry medicine Animals Humans Trypsin Serine protease biology Chemistry General Medicine Biochemistry Drug Design biology.protein Cattle Factor Xa Inhibitors Protein Binding medicine.drug |
| Zdroj: | Acta Crystallographica Section D Biological Crystallography. 55:1395-1404 |
| ISSN: | 0907-4449 |
| Popis: | 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-9065a in bovine trypsin and human factor Xa. |
| Databáze: | OpenAIRE |
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