1v3x
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(New page: 200px<br /> <applet load="1v3x" size="450" color="white" frame="true" align="right" spinBox="true" caption="1v3x, resolution 2.20Å" /> '''Factor Xa in comple...)
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Revision as of 17:34, 12 November 2007
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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
Contents |
Overview
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.
Disease
Known disease associated with this structure: Factor X deficiency OMIM:[227600]
About this Structure
1V3X is a Protein complex structure of sequences from Homo sapiens with CA and D76 as ligands. Active as Coagulation factor Xa, with EC number 3.4.21.6 Full crystallographic information is available from OCA.
Reference
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., Haginoya N, Kobayashi S, Komoriya S, Yoshino T, Suzuki M, Shimada T, Watanabe K, Hirokawa Y, Furugori T, Nagahara T, J Med Chem. 2004 Oct 7;47(21):5167-82. PMID:15456260
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