1v3x

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{{STRUCTURE_1v3x| PDB=1v3x | SCENE= }}
{{STRUCTURE_1v3x| PDB=1v3x | SCENE= }}
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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'''
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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===
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==Overview==
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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.
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(as it appears on PubMed at http://www.pubmed.gov), where 15456260 is the PubMed ID number.
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{{ABSTRACT_PUBMED_15456260}}
==About this Structure==
==About this Structure==
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==Reference==
==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:[http://www.ncbi.nlm.nih.gov/pubmed/15456260 15456260]
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:[http://www.ncbi.nlm.nih.gov/pubmed/15456260 15456260]
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Structural basis for chemical inhibition of human blood coagulation factor Xa., Kamata K, Kawamoto H, Honma T, Iwama T, Kim SH, Proc Natl Acad Sci U S A. 1998 Jun 9;95(12):6630-5. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/9618463 9618463]
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X-ray structure of active site-inhibited clotting factor Xa. Implications for drug design and substrate recognition., Brandstetter H, Kuhne A, Bode W, Huber R, von der Saal W, Wirthensohn K, Engh RA, J Biol Chem. 1996 Nov 22;271(47):29988-92. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/8939944 8939944]
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Structure of human des(1-45) factor Xa at 2.2 A resolution., Padmanabhan K, Padmanabhan KP, Tulinsky A, Park CH, Bode W, Huber R, Blankenship DT, Cardin AD, Kisiel W, J Mol Biol. 1993 Aug 5;232(3):947-66. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/8355279 8355279]
[[Category: Coagulation factor Xa]]
[[Category: Coagulation factor Xa]]
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
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[[Category: Protein inhibitor complex]]
[[Category: Protein inhibitor complex]]
[[Category: Serine protease]]
[[Category: Serine protease]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sat May 3 12:02:53 2008''
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Tue Jul 29 15:07:16 2008''

Revision as of 12:07, 29 July 2008

Image:1v3x.png

Template:STRUCTURE 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

Template:ABSTRACT PUBMED 15456260

About this Structure

1V3X is a Protein complex structure of sequences from Homo sapiens. 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

Structural basis for chemical inhibition of human blood coagulation factor Xa., Kamata K, Kawamoto H, Honma T, Iwama T, Kim SH, Proc Natl Acad Sci U S A. 1998 Jun 9;95(12):6630-5. PMID:9618463

X-ray structure of active site-inhibited clotting factor Xa. Implications for drug design and substrate recognition., Brandstetter H, Kuhne A, Bode W, Huber R, von der Saal W, Wirthensohn K, Engh RA, J Biol Chem. 1996 Nov 22;271(47):29988-92. PMID:8939944

Structure of human des(1-45) factor Xa at 2.2 A resolution., Padmanabhan K, Padmanabhan KP, Tulinsky A, Park CH, Bode W, Huber R, Blankenship DT, Cardin AD, Kisiel W, J Mol Biol. 1993 Aug 5;232(3):947-66. PMID:8355279

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