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==Human GKRP bound to AMG-2668== | ==Human GKRP bound to AMG-2668== | ||
<StructureSection load='4oho' size='340' side='right' caption='[[4oho]], [[Resolution|resolution]] 2.58Å' scene=''> | <StructureSection load='4oho' size='340' side='right'caption='[[4oho]], [[Resolution|resolution]] 2.58Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[4oho]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4OHO OCA]. For a <b>guided tour on the structure components</b> use [ | <table><tr><td colspan='2'>[[4oho]] 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=4OHO OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4OHO FirstGlance]. <br> | ||
</td></tr><tr><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=2TG:5-{[(3S)-3-(PROP-1-YN-1-YL)-4-{4-[S-(TRIFLUOROMETHYL)SULFONIMIDOYL]PHENYL}PIPERAZIN-1-YL]SULFONYL}PYRIDIN-2-AMINE'>2TG</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='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.58Å</td></tr> | ||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=2TG:5-{[(3S)-3-(PROP-1-YN-1-YL)-4-{4-[S-(TRIFLUOROMETHYL)SULFONIMIDOYL]PHENYL}PIPERAZIN-1-YL]SULFONYL}PYRIDIN-2-AMINE'>2TG</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><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[ | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4oho FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4oho OCA], [https://pdbe.org/4oho PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4oho RCSB], [https://www.ebi.ac.uk/pdbsum/4oho PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4oho ProSAT]</span></td></tr> | ||
<table> | </table> | ||
== Function == | |||
[https://www.uniprot.org/uniprot/GCKR_HUMAN GCKR_HUMAN] Inhibits glucokinase by forming an inactive complex with this enzyme. | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
We 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<ref>PMID:24611879</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 4oho" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[Glucokinase Regulatory Protein|Glucokinase Regulatory Protein]] | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: | [[Category: Homo sapiens]] | ||
[[Category: | [[Category: Large Structures]] | ||
[[Category: | [[Category: Chmait S]] | ||
[[Category: | [[Category: Jordan SR]] | ||
Latest revision as of 20:14, 20 September 2023
Human GKRP bound to AMG-2668Human GKRP bound to AMG-2668
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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