2ra0
From Proteopedia
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|PDB= 2ra0 |SIZE=350|CAPTION= <scene name='initialview01'>2ra0</scene>, resolution 2.30Å | |PDB= 2ra0 |SIZE=350|CAPTION= <scene name='initialview01'>2ra0</scene>, resolution 2.30Å | ||
|SITE= <scene name='pdbsite=AC1:Jnj+Binding+Site+For+Residue+A+1'>AC1</scene> | |SITE= <scene name='pdbsite=AC1:Jnj+Binding+Site+For+Residue+A+1'>AC1</scene> | ||
| - | |LIGAND= <scene name='pdbligand=JNJ:'>JNJ</scene> | + | |LIGAND= <scene name='pdbligand=JNJ:1-(3-AMINO-1,2-BENZISOXAZOL-5-YL)-6-(4-{2-[(DIMETHYLAMINO)METHYL]-1H-IMIDAZOL-1-YL}-2-FLUOROPHENYL)-7-FLUORO-1H-INDAZOLE-3-CARBOXAMIDE'>JNJ</scene> |
| - | |ACTIVITY= [http://en.wikipedia.org/wiki/Coagulation_factor_Xa Coagulation factor Xa], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.21.6 3.4.21.6] | + | |ACTIVITY= <span class='plainlinks'>[http://en.wikipedia.org/wiki/Coagulation_factor_Xa Coagulation factor Xa], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.21.6 3.4.21.6] </span> |
|GENE= F10 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens]) | |GENE= F10 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens]) | ||
| + | |DOMAIN= | ||
| + | |RELATEDENTRY= | ||
| + | |RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2ra0 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2ra0 OCA], [http://www.ebi.ac.uk/pdbsum/2ra0 PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=2ra0 RCSB]</span> | ||
}} | }} | ||
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==Overview== | ==Overview== | ||
We have developed a novel series of potent and selective factor Xa inhibitors that employ a key 7-fluoroindazolyl moiety. The 7-fluoro group on the indazole scaffold replaces the carbonyl group of an amide that is found in previously reported factor Xa inhibitors. The structure of a factor Xa cocrystal containing 7-fluoroindazole 51a showed the 7-fluoro atom hydrogen-bonding with the N-H of Gly216 (2.9 A) in the peptide backbone. Thus, the 7-fluoroindazolyl moiety not only occupied the same space as the carbonyl group of an amide found in prior factor Xa inhibitors but also maintained a hydrogen bond interaction with the protein's beta-sheet domain. The structure-activity relationship for this series was consistent with this finding, as the factor Xa inhibitory potencies were about 60-fold greater (DeltaDelta G approximately 2.4 kcal/mol) for the 7-fluoroindazoles 25a and 25c versus the corresponding indazoles 25b and 25d. Highly convergent synthesis of these factor Xa inhibitors is also described. | We have developed a novel series of potent and selective factor Xa inhibitors that employ a key 7-fluoroindazolyl moiety. The 7-fluoro group on the indazole scaffold replaces the carbonyl group of an amide that is found in previously reported factor Xa inhibitors. The structure of a factor Xa cocrystal containing 7-fluoroindazole 51a showed the 7-fluoro atom hydrogen-bonding with the N-H of Gly216 (2.9 A) in the peptide backbone. Thus, the 7-fluoroindazolyl moiety not only occupied the same space as the carbonyl group of an amide found in prior factor Xa inhibitors but also maintained a hydrogen bond interaction with the protein's beta-sheet domain. The structure-activity relationship for this series was consistent with this finding, as the factor Xa inhibitory potencies were about 60-fold greater (DeltaDelta G approximately 2.4 kcal/mol) for the 7-fluoroindazoles 25a and 25c versus the corresponding indazoles 25b and 25d. Highly convergent synthesis of these factor Xa inhibitors is also described. | ||
| + | |||
| + | ==Disease== | ||
| + | Known disease associated with this structure: Factor X deficiency OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=227600 227600]] | ||
==About this Structure== | ==About this Structure== | ||
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[[Category: Protein complex]] | [[Category: Protein complex]] | ||
[[Category: Abad, M C.]] | [[Category: Abad, M C.]] | ||
| - | [[Category: JNJ]] | ||
[[Category: blood coagulation]] | [[Category: blood coagulation]] | ||
[[Category: calcium]] | [[Category: calcium]] | ||
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[[Category: zymogen]] | [[Category: zymogen]] | ||
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Mar 31 04:58:01 2008'' |
Revision as of 01:58, 31 March 2008
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| , resolution 2.30Å | |||||||
|---|---|---|---|---|---|---|---|
| Sites: | |||||||
| Ligands: | |||||||
| Gene: | F10 (Homo sapiens) | ||||||
| Activity: | Coagulation factor Xa, with EC number 3.4.21.6 | ||||||
| Resources: | FirstGlance, OCA, PDBsum, RCSB | ||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||
X-ray Structure of FXa in complex with 7-fluoroindazole
Contents |
Overview
We have developed a novel series of potent and selective factor Xa inhibitors that employ a key 7-fluoroindazolyl moiety. The 7-fluoro group on the indazole scaffold replaces the carbonyl group of an amide that is found in previously reported factor Xa inhibitors. The structure of a factor Xa cocrystal containing 7-fluoroindazole 51a showed the 7-fluoro atom hydrogen-bonding with the N-H of Gly216 (2.9 A) in the peptide backbone. Thus, the 7-fluoroindazolyl moiety not only occupied the same space as the carbonyl group of an amide found in prior factor Xa inhibitors but also maintained a hydrogen bond interaction with the protein's beta-sheet domain. The structure-activity relationship for this series was consistent with this finding, as the factor Xa inhibitory potencies were about 60-fold greater (DeltaDelta G approximately 2.4 kcal/mol) for the 7-fluoroindazoles 25a and 25c versus the corresponding indazoles 25b and 25d. Highly convergent synthesis of these factor Xa inhibitors is also described.
Disease
Known disease associated with this structure: Factor X deficiency OMIM:[227600]
About this Structure
2RA0 is a Protein complex structure of sequences from Homo sapiens. Full crystallographic information is available from OCA.
Reference
7-fluoroindazoles as potent and selective inhibitors of factor Xa., Lee YK, Parks DJ, Lu T, Thieu TV, Markotan T, Pan W, McComsey DF, Milkiewicz KL, Crysler CS, Ninan N, Abad MC, Giardino EC, Maryanoff BE, Damiano BP, Player MR, J Med Chem. 2008 Jan 24;51(2):282-97. Epub 2007 Dec 27. PMID:18159923
Page seeded by OCA on Mon Mar 31 04:58:01 2008
