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{{STRUCTURE_2vh0|  PDB=2vh0  |  SCENE=  }}
===STRUCTURE AND PROPERTY BASED DESIGN OF FACTOR XA INHIBITORS: BIARYL PYRROLIDIN-2-ONES INCORPORATING BASIC HETEROCYCLIC MOTIFS===
{{ABSTRACT_PUBMED_18053714}}


==Disease==
==Structure and property based design of factor Xa inhibitors:biaryl pyrrolidin-2-ones incorporating basic heterocyclic motifs==
[[http://www.uniprot.org/uniprot/FA10_HUMAN FA10_HUMAN]] Defects in F10 are the cause of factor X deficiency (FA10D) [MIM:[http://omim.org/entry/227600 227600]]. A hemorrhagic disease with variable presentation. Affected individuals can manifest prolonged nasal and mucosal hemorrhage, menorrhagia, hematuria, and occasionally hemarthrosis. Some patients do not have clinical bleeding diathesis.<ref>PMID:2790181</ref><ref>PMID:1973167</ref><ref>PMID:1985698</ref><ref>PMID:7669671</ref><ref>PMID:8529633</ref><ref>PMID:7860069</ref><ref>PMID:8845463</ref><ref>PMID:8910490</ref><ref>PMID:10468877</ref><ref>PMID:10746568</ref><ref>PMID:10739379</ref><ref>PMID:11248282</ref><ref>PMID:11728527</ref><ref>PMID:12945883</ref><ref>PMID:15650540</ref><ref>PMID:17393015</ref><ref>PMID:19135706</ref>  
<StructureSection load='2vh0' size='340' side='right'caption='[[2vh0]], [[Resolution|resolution]] 1.70&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[2vh0]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2VH0 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2VH0 FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.7&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=GSI:2-(5-CHLOROTHIOPHEN-2-YL)-N-[(3S)-1-(4-{2-[(DIMETHYLAMINO)METHYL]-1H-IMIDAZOL-1-YL}-2-FLUOROPHENYL)-2-OXOPYRROLIDIN-3-YL]ETHANESULFONAMIDE'>GSI</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=2vh0 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2vh0 OCA], [https://pdbe.org/2vh0 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2vh0 RCSB], [https://www.ebi.ac.uk/pdbsum/2vh0 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2vh0 ProSAT]</span></td></tr>
</table>
== Disease ==
[https://www.uniprot.org/uniprot/FA10_HUMAN FA10_HUMAN] Defects in F10 are the cause of factor X deficiency (FA10D) [MIM:[https://omim.org/entry/227600 227600]. A hemorrhagic disease with variable presentation. Affected individuals can manifest prolonged nasal and mucosal hemorrhage, menorrhagia, hematuria, and occasionally hemarthrosis. Some patients do not have clinical bleeding diathesis.<ref>PMID:2790181</ref> <ref>PMID:1973167</ref> <ref>PMID:1985698</ref> <ref>PMID:7669671</ref> <ref>PMID:8529633</ref> <ref>PMID:7860069</ref> <ref>PMID:8845463</ref> <ref>PMID:8910490</ref> <ref>PMID:10468877</ref> <ref>PMID:10746568</ref> <ref>PMID:10739379</ref> <ref>PMID:11248282</ref> <ref>PMID:11728527</ref> <ref>PMID:12945883</ref> <ref>PMID:15650540</ref> <ref>PMID:17393015</ref> <ref>PMID:19135706</ref>  
== Function ==
[https://www.uniprot.org/uniprot/FA10_HUMAN FA10_HUMAN] Factor Xa is a vitamin K-dependent glycoprotein that converts prothrombin to thrombin in the presence of factor Va, calcium and phospholipid during blood clotting.
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Structure and property based drug design was exploited in the synthesis of sulfonamidopyrrolidin-2-one-based factor Xa (fXa) inhibitors, incorporating basic biaryl P4 groups, producing highly potent inhibitors with significant anticoagulant activities and encouraging oral pharmacokinetic profiles.


==Function==
Structure and property based design of factor Xa inhibitors: biaryl pyrrolidin-2-ones incorporating basic heterocyclic motifs.,Young RJ, Borthwick AD, Brown D, Burns-Kurtis CL, Campbell M, Chan C, Charbaut M, Convery MA, Diallo H, Hortense E, Irving WR, Kelly HA, King NP, Kleanthous S, Mason AM, Pateman AJ, Patikis AN, Pinto IL, Pollard DR, Senger S, Shah GP, Toomey JR, Watson NS, Weston HE, Zhou P Bioorg Med Chem Lett. 2008 Jan 1;18(1):28-33. Epub 2007 Nov 13. PMID:18053714<ref>PMID:18053714</ref>
[[http://www.uniprot.org/uniprot/FA10_HUMAN FA10_HUMAN]] Factor Xa is a vitamin K-dependent glycoprotein that converts prothrombin to thrombin in the presence of factor Va, calcium and phospholipid during blood clotting.  


==About this Structure==
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
[[2vh0]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2VH0 OCA].
</div>
<div class="pdbe-citations 2vh0" style="background-color:#fffaf0;"></div>


==See Also==
==See Also==
*[[Factor Xa|Factor Xa]]
*[[Factor Xa|Factor Xa]]
 
== References ==
==Reference==
<references/>
<ref group="xtra">PMID:018053714</ref><references group="xtra"/><references/>
__TOC__
[[Category: Coagulation factor Xa]]
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
[[Category: Borthwick, A D.]]
[[Category: Large Structures]]
[[Category: Brown, D.]]
[[Category: Borthwick AD]]
[[Category: Burns-Kurtis, C L.]]
[[Category: Brown D]]
[[Category: Campbell, M.]]
[[Category: Burns-Kurtis CL]]
[[Category: Chan, C.]]
[[Category: Campbell M]]
[[Category: Charbaut, M.]]
[[Category: Chan C]]
[[Category: Convery, M A.]]
[[Category: Charbaut M]]
[[Category: Diallo, H.]]
[[Category: Convery MA]]
[[Category: Hortense, E.]]
[[Category: Diallo H]]
[[Category: Irving, W R.]]
[[Category: Hortense E]]
[[Category: Kelly, H A.]]
[[Category: Irving WR]]
[[Category: King, N P.]]
[[Category: Kelly HA]]
[[Category: Kleanthous, S.]]
[[Category: King NP]]
[[Category: Mason, A M.]]
[[Category: Kleanthous S]]
[[Category: Pateman, A J.]]
[[Category: Mason AM]]
[[Category: Patikis, A.]]
[[Category: Pateman AJ]]
[[Category: Pinto, I L.]]
[[Category: Patikis A]]
[[Category: Pollard, D R.]]
[[Category: Pinto IL]]
[[Category: Senger, S.]]
[[Category: Pollard DR]]
[[Category: Shah, G P.]]
[[Category: Senger S]]
[[Category: Toomey, J R.]]
[[Category: Shah GP]]
[[Category: Watson, N S.]]
[[Category: Toomey JR]]
[[Category: Weston, H E.]]
[[Category: Watson NS]]
[[Category: Young, R J.]]
[[Category: Weston HE]]
[[Category: Zhou, P.]]
[[Category: Young RJ]]
[[Category: Blood coagulation]]
[[Category: Zhou P]]
[[Category: Cleavage on pair of basic residue]]
[[Category: Complex]]
[[Category: Egf-like domain]]
[[Category: Gamma-carboxyglutamic acid]]
[[Category: Glycoprotein]]
[[Category: Hydrolase]]
[[Category: Hydroxylation]]
[[Category: Protease]]
[[Category: Serine protease]]
[[Category: Zymogen]]

Latest revision as of 12:32, 6 November 2024

Structure and property based design of factor Xa inhibitors:biaryl pyrrolidin-2-ones incorporating basic heterocyclic motifsStructure and property based design of factor Xa inhibitors:biaryl pyrrolidin-2-ones incorporating basic heterocyclic motifs

Structural highlights

2vh0 is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 1.7Å
Ligands:, ,
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

FA10_HUMAN Defects in F10 are the cause of factor X deficiency (FA10D) [MIM:227600. A hemorrhagic disease with variable presentation. Affected individuals can manifest prolonged nasal and mucosal hemorrhage, menorrhagia, hematuria, and occasionally hemarthrosis. Some patients do not have clinical bleeding diathesis.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17]

Function

FA10_HUMAN Factor Xa is a vitamin K-dependent glycoprotein that converts prothrombin to thrombin in the presence of factor Va, calcium and phospholipid during blood clotting.

Publication Abstract from PubMed

Structure and property based drug design was exploited in the synthesis of sulfonamidopyrrolidin-2-one-based factor Xa (fXa) inhibitors, incorporating basic biaryl P4 groups, producing highly potent inhibitors with significant anticoagulant activities and encouraging oral pharmacokinetic profiles.

Structure and property based design of factor Xa inhibitors: biaryl pyrrolidin-2-ones incorporating basic heterocyclic motifs.,Young RJ, Borthwick AD, Brown D, Burns-Kurtis CL, Campbell M, Chan C, Charbaut M, Convery MA, Diallo H, Hortense E, Irving WR, Kelly HA, King NP, Kleanthous S, Mason AM, Pateman AJ, Patikis AN, Pinto IL, Pollard DR, Senger S, Shah GP, Toomey JR, Watson NS, Weston HE, Zhou P Bioorg Med Chem Lett. 2008 Jan 1;18(1):28-33. Epub 2007 Nov 13. PMID:18053714[18]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

See Also

References

  1. ↑ Reddy SV, Zhou ZQ, Rao KJ, Scott JP, Watzke H, High KA, Jagadeeswaran P. Molecular characterization of human factor XSan Antonio. Blood. 1989 Oct;74(5):1486-90. PMID:2790181
  2. ↑ Watzke HH, Lechner K, Roberts HR, Reddy SV, Welsch DJ, Friedman P, Mahr G, Jagadeeswaran P, Monroe DM, High KA. Molecular defect (Gla+14----Lys) and its functional consequences in a hereditary factor X deficiency (factor X "Vorarlberg"). J Biol Chem. 1990 Jul 15;265(20):11982-9. PMID:1973167
  3. ↑ James HL, Girolami A, Fair DS. Molecular defect in coagulation factor XFriuli results from a substitution of serine for proline at position 343. Blood. 1991 Jan 15;77(2):317-23. PMID:1985698
  4. ↑ Marchetti G, Castaman G, Pinotti M, Lunghi B, Di Iasio MG, Ruggieri M, Rodeghiero F, Bernardi F. Molecular bases of CRM+ factor X deficiency: a frequent mutation (Ser334Pro) in the catalytic domain and a substitution (Glu102Lys) in the second EGF-like domain. Br J Haematol. 1995 Aug;90(4):910-5. PMID:7669671
  5. ↑ Bezeaud A, Miyata T, Helley D, Zeng YZ, Kato H, Aillaud MF, Juhan-Vague I, Guillin MC. Functional consequences of the Ser334-->Pro mutation in a human factor X variant (factor XMarseille). Eur J Biochem. 1995 Nov 15;234(1):140-7. PMID:8529633
  6. ↑ Kim DJ, Thompson AR, James HL. Factor XKetchikan: a variant molecule in which Gly replaces a Gla residue at position 14 in the light chain. Hum Genet. 1995 Feb;95(2):212-4. PMID:7860069
  7. ↑ Messier TL, Wong CY, Bovill EG, Long GL, Church WR. Factor X Stockton: a mild bleeding diathesis associated with an active site mutation in factor X. Blood Coagul Fibrinolysis. 1996 Jan;7(1):5-14. PMID:8845463
  8. ↑ Rudolph AE, Mullane MP, Porche-Sorbet R, Tsuda S, Miletich JP. Factor XSt. Louis II. Identification of a glycine substitution at residue 7 and characterization of the recombinant protein. J Biol Chem. 1996 Nov 8;271(45):28601-6. PMID:8910490
  9. ↑ Zama T, Murata M, Watanabe R, Yokoyama K, Moriki T, Ambo H, Murakami H, Kikuchi M, Ikeda Y. A family with hereditary factor X deficiency with a point mutation Gla32 to Gln in the Gla domain (factor X Tokyo). Br J Haematol. 1999 Sep;106(3):809-11. PMID:10468877
  10. ↑ Millar DS, Elliston L, Deex P, Krawczak M, Wacey AI, Reynaud J, Nieuwenhuis HK, Bolton-Maggs P, Mannucci PM, Reverter JC, Cachia P, Pasi KJ, Layton DM, Cooper DN. Molecular analysis of the genotype-phenotype relationship in factor X deficiency. Hum Genet. 2000 Feb;106(2):249-57. PMID:10746568
  11. ↑ Forberg E, Huhmann I, Jimenez-Boj E, Watzke HH. The impact of Glu102Lys on the factor X function in a patient with a doubly homozygous factor X deficiency (Gla14Lys and Glu102Lys). Thromb Haemost. 2000 Feb;83(2):234-8. PMID:10739379
  12. ↑ Simioni P, Vianello F, Kalafatis M, Barzon L, Ladogana S, Paolucci P, Carotenuto M, Dal Bello F, Palu G, Girolami A. A dysfunctional factor X (factor X San Giovanni Rotondo) present at homozygous and double heterozygous level: identification of a novel microdeletion (delC556) and missense mutation (Lys(408)-->Asn) in the factor X gene. A study of an Italian family. Thromb Res. 2001 Feb 15;101(4):219-30. PMID:11248282
  13. ↑ Vianello F, Lombardi AM, Boldrin C, Luni S, Girolami A. A new factor X defect (factor X Padua 3): a compound heterozygous between true deficiency (Gly(380)-->Arg) and an abnormality (Ser(334)-->Pro). Thromb Res. 2001 Nov 15;104(4):257-64. PMID:11728527
  14. ↑ Vianello F, Lombardi AM, Bello FD, Palu G, Zanon E, Girolami A. A novel type I factor X variant (factor X Cys350Phe) due to loss of a disulfide bond in the catalytic domain. Blood Coagul Fibrinolysis. 2003 Jun;14(4):401-5. PMID:12945883
  15. ↑ Isshiki I, Favier R, Moriki T, Uchida T, Ishihara H, Van Dreden P, Murata M, Ikeda Y. Genetic analysis of hereditary factor X deficiency in a French patient of Sri Lankan ancestry: in vitro expression study identified Gly366Ser substitution as the molecular basis of the dysfunctional factor X. Blood Coagul Fibrinolysis. 2005 Jan;16(1):9-16. PMID:15650540
  16. ↑ Al-Hilali A, Wulff K, Abdel-Razeq H, Saud KA, Al-Gaili F, Herrmann FH. Analysis of the novel factor X gene mutation Glu51Lys in two families with factor X-Riyadh anomaly. Thromb Haemost. 2007 Apr;97(4):542-5. PMID:17393015
  17. ↑ Chafa O, Tagzirt M, Tapon-Bretaudiere J, Reghis A, Fischer AM, LeBonniec BF. Characterization of a homozygous Gly11Val mutation in the Gla domain of coagulation factor X. Thromb Res. 2009 May;124(1):144-8. doi: 10.1016/j.thromres.2008.11.018. Epub 2009, Jan 10. PMID:19135706 doi:10.1016/j.thromres.2008.11.018
  18. ↑ Young RJ, Borthwick AD, Brown D, Burns-Kurtis CL, Campbell M, Chan C, Charbaut M, Convery MA, Diallo H, Hortense E, Irving WR, Kelly HA, King NP, Kleanthous S, Mason AM, Pateman AJ, Patikis AN, Pinto IL, Pollard DR, Senger S, Shah GP, Toomey JR, Watson NS, Weston HE, Zhou P. Structure and property based design of factor Xa inhibitors: biaryl pyrrolidin-2-ones incorporating basic heterocyclic motifs. Bioorg Med Chem Lett. 2008 Jan 1;18(1):28-33. Epub 2007 Nov 13. PMID:18053714 doi:S0960-894X(07)01328-5

2vh0, resolution 1.70Å

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