4ohp: Difference between revisions
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== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[4ohp]] 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=4OHP OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4OHP FirstGlance]. <br> | <table><tr><td colspan='2'>[[4ohp]] 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=4OHP OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4OHP FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=2TJ:4-[(2S)-4-[(6-AMINOPYRIDIN-3-YL)SULFONYL]-2-(PROP-1-YN-1-YL)PIPERAZIN-1-YL]-N-METHYLBENZENESULFONAMIDE'>2TJ</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=IOD:IODIDE+ION'>IOD</scene>, <scene name='pdbligand=S6P:D-SORBITOL-6-PHOSPHATE'>S6P</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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]] 2.4Å</td></tr> | ||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=2TJ:4-[(2S)-4-[(6-AMINOPYRIDIN-3-YL)SULFONYL]-2-(PROP-1-YN-1-YL)PIPERAZIN-1-YL]-N-METHYLBENZENESULFONAMIDE'>2TJ</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=IOD:IODIDE+ION'>IOD</scene>, <scene name='pdbligand=S6P:D-SORBITOL-6-PHOSPHATE'>S6P</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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=4ohp FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4ohp OCA], [https://pdbe.org/4ohp PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4ohp RCSB], [https://www.ebi.ac.uk/pdbsum/4ohp PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4ohp ProSAT]</span></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=4ohp FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4ohp OCA], [https://pdbe.org/4ohp PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4ohp RCSB], [https://www.ebi.ac.uk/pdbsum/4ohp PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4ohp ProSAT]</span></td></tr> | ||
</table> | </table> | ||
Latest revision as of 20:14, 20 September 2023
Human GKRP bound to AMG-3227 and S6PHuman GKRP bound to AMG-3227 and S6P
Structural highlights
FunctionGCKR_HUMAN Inhibits glucokinase by forming an inactive complex with this enzyme. Publication Abstract from PubMedWe have recently reported a novel approach to increase cytosolic glucokinase (GK) levels through the binding of a small molecule to its endogenous inhibitor, glucokinase regulatory protein (GKRP). These initial investigations culminated in the identification of 2-(4-((2S)-4-((6-amino-3-pyridinyl)sulfonyl)-2-(1-propyn-1-yl)-1-piperazinyl)phen yl)-1,1,1,3,3,3-hexafluoro-2-propanol (1, AMG-3969), a compound that effectively enhanced GK translocation and reduced blood glucose levels in diabetic animals. Herein we report the results of our expanded SAR investigations that focused on modifications to the aryl carbinol group of this series. Guided by the X-ray cocrystal structure of compound 1 bound to hGKRP, we identified several potent GK-GKRP disruptors bearing a diverse set of functionalities in the aryl carbinol region. Among them, sulfoximine and pyridinyl derivatives 24 and 29 possessed excellent potency as well as favorable PK properties. When dosed orally in db/db mice, both compounds significantly lowered fed blood glucose levels (up to 58%). Small molecule disruptors of the glucokinase-glucokinase regulatory protein interaction: 3. Structure-activity relationships within the aryl carbinol region of the N-arylsulfonamido-N'-arylpiperazine series.,Nishimura N, Norman MH, Liu L, Yang KC, Ashton KS, Bartberger MD, Chmait S, Chen J, Cupples R, Fotsch C, Helmering J, Jordan SR, Kunz RK, Pennington LD, Poon SF, Siegmund A, Sivits G, Lloyd DJ, Hale C, St Jean DJ Jr J Med Chem. 2014 Apr 10;57(7):3094-116. doi: 10.1021/jm5000497. Epub 2014 Mar 31. PMID:24611879[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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