4fcq: Difference between revisions

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 ==Targeting conserved water molecules: Design of 4-aryl-5-cyanopyrrolo[2,3-d]pyrimidine Hsp90 inhibitors using fragment-based screening and structure-based optimization==
-<StructureSection load='4fcq' size='340' side='right' caption='[[4fcq]], [[Resolution|resolution]] 2.15&Aring;' scene=''>
+<StructureSection load='4fcq' size='340' side='right'caption='[[4fcq]], [[Resolution|resolution]] 2.15&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[4fcq]] is a 1 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=4FCQ OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4FCQ FirstGlance]. <br>
+<table><tr><td colspan='2'>[[4fcq]] is a 1 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=4FCQ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4FCQ FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=2N6:4-(2,4-DIMETHYLPHENYL)-2-(METHYLSULFANYL)-7H-PYRROLO[2,3-D]PYRIMIDINE-5-CARBONITRILE'>2N6</scene></td></tr>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.151&#8491;</td></tr>
-<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4fcp|4fcp]], [[4fcr|4fcr]]</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=2N6:4-(2,4-DIMETHYLPHENYL)-2-(METHYLSULFANYL)-7H-PYRROLO[2,3-D]PYRIMIDINE-5-CARBONITRILE'>2N6</scene></td></tr>
-<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">HSP90AA1, HSP90A, HSPC1, HSPCA ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])</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=4fcq FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4fcq OCA], [https://pdbe.org/4fcq PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4fcq RCSB], [https://www.ebi.ac.uk/pdbsum/4fcq PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4fcq ProSAT]</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=4fcq FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4fcq OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4fcq RCSB], [http://www.ebi.ac.uk/pdbsum/4fcq PDBsum]</span></td></tr>
 </table>
 == Function ==
-[[http://www.uniprot.org/uniprot/HS90A_HUMAN HS90A_HUMAN]] Molecular chaperone that promotes the maturation, structural maintenance and proper regulation of specific target proteins involved for instance in cell cycle control and signal transduction. Undergoes a functional cycle that is linked to its ATPase activity. This cycle probably induces conformational changes in the client proteins, thereby causing their activation. Interacts dynamically with various co-chaperones that modulate its substrate recognition, ATPase cycle and chaperone function.<ref>PMID:15937123</ref> <ref>PMID:11274138</ref>
+[https://www.uniprot.org/uniprot/HS90A_HUMAN HS90A_HUMAN] Molecular chaperone that promotes the maturation, structural maintenance and proper regulation of specific target proteins involved for instance in cell cycle control and signal transduction. Undergoes a functional cycle that is linked to its ATPase activity. This cycle probably induces conformational changes in the client proteins, thereby causing their activation. Interacts dynamically with various co-chaperones that modulate its substrate recognition, ATPase cycle and chaperone function.<ref>PMID:15937123</ref> <ref>PMID:11274138</ref>
-<div style="background-color:#fffaf0;">
-== Publication Abstract from PubMed ==
-Inhibitors of the Hsp90 molecular chaperone are showing promise as anti-cancer agents. Here we describe a series of 4-aryl-5-cyanopyrrolo[2,3-d]pyrimidine ATP competitive Hsp90 inhibitors that were identified following structure-driven optimization of purine hits revealed by NMR based screening of a proprietary fragment library. Ligand-Hsp90 X-ray structures combined with molecular modeling led to the rational displacement of a conserved water molecule leading to enhanced affinity for Hsp90 as measured by fluorescence polarization, isothermal titration calorimetry and surface plasmon resonance assays. This displacement was achieved with a nitrile group, presenting an example of efficient gain in binding affinity with minimal increase in molecular weight. Some compounds in this chemical series inhibit the proliferation of human cancer cell lines in vitro and cause depletion of oncogenic Hsp90 client proteins and concomitant elevation of the co-chaperone Hsp70. In addition, one compound was demonstrated to be orally bioavailable in the mouse. This work demonstrates the power of structure-based design for the rapid evolution of potent Hsp90 inhibitors and the importance of considering conserved water molecules in drug design.
-Targeting conserved water molecules: Design of 4-aryl-5-cyanopyrrolo[2,3-d]pyrimidine Hsp90 inhibitors using fragment-based screening and structure-based optimization.,Davies NG, Browne H, Davis B, Drysdale MJ, Foloppe N, Geoffrey S, Gibbons B, Hart T, Hubbard R, Jensen MR, Mansell H, Massey A, Matassova N, Moore JD, Murray J, Pratt R, Ray S, Robertson A, Roughley SD, Schoepfer J, Scriven K, Simmonite H, Stokes S, Surgenor A, Webb P, Wood M, Wright L, Brough P Bioorg Med Chem. 2012 Nov 15;20(22):6770-89. doi: 10.1016/j.bmc.2012.08.050. Epub, 2012 Sep 4. PMID:23018093<ref>PMID:23018093</ref>
-From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-</div>
 ==See Also==
-*[[Heat Shock Proteins|Heat Shock Proteins]]
+*[[Heat Shock Protein structures|Heat Shock Protein structures]]
 == References ==
 <references/>
@@ Line 26: / Line 18: @@
 </StructureSection>
 [[Category: Homo sapiens]]
-[[Category: Brough, P]]
+[[Category: Large Structures]]
-[[Category: Browne, H]]
+[[Category: Brough P]]
-[[Category: Davies, N G]]
+[[Category: Browne H]]
-[[Category: Davis, B]]
+[[Category: Davies NG]]
-[[Category: Drysdale, M J]]
+[[Category: Davis B]]
-[[Category: Foloppe, N]]
+[[Category: Drysdale MJ]]
-[[Category: Geoffrey, S]]
+[[Category: Foloppe N]]
-[[Category: Gibbons, B]]
+[[Category: Geoffrey S]]
-[[Category: Hart, T]]
+[[Category: Gibbons B]]
-[[Category: Jensen, M R]]
+[[Category: Hart T]]
-[[Category: Mansell, H]]
+[[Category: Jensen MR]]
-[[Category: Massey, A]]
+[[Category: Mansell H]]
-[[Category: Matassova, N]]
+[[Category: Massey A]]
-[[Category: Moore, J D]]
+[[Category: Matassova N]]
-[[Category: Murray, J]]
+[[Category: Moore JD]]
-[[Category: Pratt, R]]
+[[Category: Murray J]]
-[[Category: Ray, S]]
+[[Category: Pratt R]]
-[[Category: Roughley, S D]]
+[[Category: Ray S]]
-[[Category: Schoepfer, J]]
+[[Category: Roughley SD]]
-[[Category: Scriven, K]]
+[[Category: Schoepfer J]]
-[[Category: Simmonite, H]]
+[[Category: Scriven K]]
-[[Category: Stokes, S]]
+[[Category: Simmonite H]]
-[[Category: Surgenor, A]]
+[[Category: Stokes S]]
-[[Category: Webb, P]]
+[[Category: Surgenor A]]
-[[Category: Wright, L]]
+[[Category: Webb P]]
-[[Category: Atpase]]
+[[Category: Wright L]]
-[[Category: Chaperone]]
-[[Category: Fragment]]
-[[Category: Heat shock protein]]
-[[Category: Hsp90]]
-[[Category: Structure-based design]]