4cra: Difference between revisions

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-'''Unreleased structure'''
+==Creating novel F1 inhibitors through fragment based lead generation and structure aided drug design==
+<StructureSection load='4cra' size='340' side='right' caption='[[4cra]], [[Resolution|resolution]] 1.80&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[4cra]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4CRA OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4CRA FirstGlance]. <br>
+</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=XJ8:N-[(1S)-2-[(2-AMINO-5-QUINOLYL)METHYLAMINO]-1-BENZYL-2-OXO-ETHYL]-4-HYDROXY-2-OXO-1H-QUINOLINE-6-CARBOXAMIDE'>XJ8</scene></td></tr>
+<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4cr5|4cr5]], [[4cr9|4cr9]], [[4crb|4crb]], [[4crc|4crc]], [[4crd|4crd]], [[4cre|4cre]], [[4crf|4crf]], [[4crg|4crg]]</td></tr>
+<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Coagulation_factor_XIa Coagulation factor XIa], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.21.27 3.4.21.27] </span></td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4cra FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4cra OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4cra RCSB], [http://www.ebi.ac.uk/pdbsum/4cra PDBsum]</span></td></tr>
+</table>
+== Disease ==
+[[http://www.uniprot.org/uniprot/FA11_HUMAN FA11_HUMAN]] Defects in F11 are the cause of factor XI deficiency (FA11D) [MIM:[http://omim.org/entry/612416 612416]]; also known as plasma thromboplastin antecedent deficiency or Rosenthal syndrome. It is a hemorrhagic disease characterized by reduced levels and activity of factor XI resulting in moderate bleeding symptoms, usually occurring after trauma or surgery. Patients usually do not present spontaneous bleeding but women can present with menorrhagia. Hemorrhages are usually moderate.<ref>PMID:2813350</ref> <ref>PMID:1547342</ref> <ref>PMID:7888672</ref> <ref>PMID:7669672</ref> <ref>PMID:9401068</ref> <ref>PMID:9787168</ref> <ref>PMID:10027710</ref> <ref>PMID:10606881</ref> <ref>PMID:11895778</ref> <ref>PMID:15026311</ref> <ref>PMID:15180874</ref> <ref>PMID:15953011</ref> <ref>PMID:16607084</ref> <ref>PMID:18005151</ref> <ref>PMID:21668437</ref> <ref>PMID:21457405</ref> <ref>PMID:22016685</ref> <ref>PMID:22322133</ref> <ref>PMID:21999818</ref> <ref>PMID:22159456</ref>
+== Function ==
+[[http://www.uniprot.org/uniprot/FA11_HUMAN FA11_HUMAN]] Factor XI triggers the middle phase of the intrinsic pathway of blood coagulation by activating factor IX.
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+Activated factor XI (FXIa) inhibitors are anticipated to combine anticoagulant and profibrinolytic effects with a low bleeding risk. This motivated a structure aided fragment based lead generation campaign to create novel FXIa inhibitor leads. A virtual screen, based on docking experiments, was performed to generate a FXIa targeted fragment library for an NMR screen that resulted in the identification of fragments binding in the FXIa S1 binding pocket. The neutral 6-chloro-3,4-dihydro-1H-quinolin-2-one and the weakly basic quinolin-2-amine structures are novel FXIa P1 fragments. The expansion of these fragments towards the FXIa prime side binding sites was aided by solving the X-ray structures of reported FXIa inhibitors that we found to bind in the S1-S1'-S2' FXIa binding pockets. Combining the X-ray structure information from the identified S1 binding 6-chloro-3,4-dihydro-1H-quinolin-2-one fragment and the S1-S1'-S2' binding reference compounds enabled structure guided linking and expansion work to achieve one of the most potent and selective FXIa inhibitors reported to date, compound 13, with a FXIa IC50 of 1.0 nM. The hydrophilicity and large polar surface area of the potent S1-S1'-S2' binding FXIa inhibitors compromised permeability. Initial work to expand the 6-chloro-3,4-dihydro-1H-quinolin-2-one fragment towards the prime side to yield molecules with less hydrophilicity shows promise to afford potent, selective and orally bioavailable compounds.
-The entry 4cra is ON HOLD  until Paper Publication
+Creating Novel Activated Factor XI Inhibitors through Fragment Based Lead Generation and Structure Aided Drug Design.,Fjellstrom O, Akkaya S, Beisel HG, Eriksson PO, Erixon K, Gustafsson D, Jurva U, Kang D, Karis D, Knecht W, Nerme V, Nilsson I, Olsson T, Redzic A, Roth R, Sandmark J, Tigerstrom A, Oster L PLoS One. 2015 Jan 28;10(1):e0113705. doi: 10.1371/journal.pone.0113705., eCollection 2015. PMID:25629509<ref>PMID:25629509</ref>
-Authors: Sandmark, J., Oster, L., Fjellstrom, O., Akkaya, S., Beisel, H.G., Eriksson, P.O., Erixon, K., Gustafsson, D., Jurva, U., Kang, D., Karis, D., Knecht, W., Nerme, V., Nilsson, I., Olsson, T., Redzic, A., Roth, R., Tigerstrom, A.
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
+</div>
-Description: Creating novel F1 inhibitors through fragment based lead generation and structure aided drug design
+== References ==
-[[Category: Unreleased Structures]]
+<references/>
-[[Category: Tigerstrom, A]]
+__TOC__
-[[Category: Roth, R]]
+</StructureSection>
+[[Category: Coagulation factor XIa]]
+[[Category: Akkaya, S]]
+[[Category: Beisel, H G]]
+[[Category: Eriksson, P O]]
+[[Category: Erixon, K]]
+[[Category: Fjellstrom, O]]
 [[Category: Gustafsson, D]]
-[[Category: Nilsson, I]]
+[[Category: Jurva, U]]
 [[Category: Kang, D]]
 [[Category: Karis, D]]
-[[Category: Oster, L]]
-[[Category: Akkaya, S]]
-[[Category: Olsson, T]]
 [[Category: Knecht, W]]
-[[Category: Beisel, H.G]]
 [[Category: Nerme, V]]
-[[Category: Jurva, U]]
+[[Category: Nilsson, I]]
-[[Category: Erixon, K]]
+[[Category: Olsson, T]]
-[[Category: Fjellstrom, O]]
+[[Category: Oster, L]]
-[[Category: Eriksson, P.O]]
 [[Category: Redzic, A]]
+[[Category: Roth, R]]
 [[Category: Sandmark, J]]
+[[Category: Tigerstrom, A]]
+[[Category: Hydrolase]]