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==Structure of KHK in complex with compound 4 (6-[(1~{S},5~{R})-6-(hydroxymethyl)-3-azabicyclo[3.1.0]hexan-3-yl]-2-[(2~{S},3~{R})-2-methyl-3-oxidanyl-azetidin-1-yl]-4-(trifluoromethyl)pyridine-3-carbonitrile)== | ==Structure of KHK in complex with compound 4 (6-[(1~{S},5~{R})-6-(hydroxymethyl)-3-azabicyclo[3.1.0]hexan-3-yl]-2-[(2~{S},3~{R})-2-methyl-3-oxidanyl-azetidin-1-yl]-4-(trifluoromethyl)pyridine-3-carbonitrile)== | ||
<StructureSection load='6w0x' size='340' side='right'caption='[[6w0x]]' scene=''> | <StructureSection load='6w0x' size='340' side='right'caption='[[6w0x]], [[Resolution|resolution]] 2.38Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6W0X OCA]. For a <b>guided tour on the structure components</b> use [ | <table><tr><td colspan='2'>[[6w0x]] 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=6W0X OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6W0X FirstGlance]. <br> | ||
</td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[ | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.38Å</td></tr> | ||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=S6J:6-[(1~{S},5~{R})-6-(hydroxymethyl)-3-azabicyclo[3.1.0]hexan-3-yl]-2-[(2~{S},3~{R})-2-methyl-3-oxidanyl-azetidin-1-yl]-4-(trifluoromethyl)pyridine-3-carbonitrile'>S6J</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=6w0x FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6w0x OCA], [https://pdbe.org/6w0x PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6w0x RCSB], [https://www.ebi.ac.uk/pdbsum/6w0x PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6w0x ProSAT]</span></td></tr> | |||
</table> | </table> | ||
== Disease == | |||
[https://www.uniprot.org/uniprot/KHK_HUMAN KHK_HUMAN] Defects in KHK are the cause of fructosuria (FRUCT) [MIM:[https://omim.org/entry/229800 229800]. Benign defect of intermediary metabolism.<ref>PMID:19237742</ref> <ref>PMID:7833921</ref> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/KHK_HUMAN KHK_HUMAN] | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Increased fructose consumption and its subsequent metabolism have been implicated in metabolic disorders such as nonalcoholic fatty liver disease and steatohepatitis (NAFLD/NASH) and insulin resistance. Ketohexokinase (KHK) converts fructose to fructose-1-phosphate (F1P) in the first step of the metabolic cascade. Herein we report the discovery of a first-in-class KHK inhibitor, PF-06835919 (8), currently in phase 2 clinical trials. The discovery of 8 was built upon our originally reported, fragment-derived lead 1 and the recognition of an alternative, rotated binding mode upon changing the ribose-pocket binding moiety from a pyrrolidinyl to an azetidinyl ring system. This new binding mode enabled efficient exploration of the vector directed at the Arg-108 residue, leading to the identification of highly potent 3-azabicyclo[3.1.0]hexane acetic acid-based KHK inhibitors by combined use of parallel medicinal chemistry and structure-based drug design. | |||
Discovery of PF-06835919: A Potent Inhibitor of Ketohexokinase (KHK) for the Treatment of Metabolic Disorders Driven by the Overconsumption of Fructose.,Futatsugi K, Smith AC, Tu M, Raymer B, Ahn K, Coffey SB, Dowling MS, Fernando DP, Gutierrez JA, Huard K, Jasti J, Kalgutkar AS, Knafels JD, Pandit J, Parris KD, Perez S, Pfefferkorn JA, Price DA, Ryder T, Shavnya A, Stock IA, Tsai AS, Tesz GJ, Thuma BA, Weng Y, Wisniewska HM, Xing G, Zhou J, Magee TV J Med Chem. 2020 Sep 27. doi: 10.1021/acs.jmedchem.0c00944. PMID:32910646<ref>PMID:32910646</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 6w0x" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[Ketohexokinase|Ketohexokinase]] | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Homo sapiens]] | |||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Jasti J]] | [[Category: Jasti J]] | ||
Latest revision as of 11:24, 11 October 2023
Structure of KHK in complex with compound 4 (6-[(1~{S},5~{R})-6-(hydroxymethyl)-3-azabicyclo[3.1.0]hexan-3-yl]-2-[(2~{S},3~{R})-2-methyl-3-oxidanyl-azetidin-1-yl]-4-(trifluoromethyl)pyridine-3-carbonitrile)Structure of KHK in complex with compound 4 (6-[(1~{S},5~{R})-6-(hydroxymethyl)-3-azabicyclo[3.1.0]hexan-3-yl]-2-[(2~{S},3~{R})-2-methyl-3-oxidanyl-azetidin-1-yl]-4-(trifluoromethyl)pyridine-3-carbonitrile)
Structural highlights
DiseaseKHK_HUMAN Defects in KHK are the cause of fructosuria (FRUCT) [MIM:229800. Benign defect of intermediary metabolism.[1] [2] FunctionPublication Abstract from PubMedIncreased fructose consumption and its subsequent metabolism have been implicated in metabolic disorders such as nonalcoholic fatty liver disease and steatohepatitis (NAFLD/NASH) and insulin resistance. Ketohexokinase (KHK) converts fructose to fructose-1-phosphate (F1P) in the first step of the metabolic cascade. Herein we report the discovery of a first-in-class KHK inhibitor, PF-06835919 (8), currently in phase 2 clinical trials. The discovery of 8 was built upon our originally reported, fragment-derived lead 1 and the recognition of an alternative, rotated binding mode upon changing the ribose-pocket binding moiety from a pyrrolidinyl to an azetidinyl ring system. This new binding mode enabled efficient exploration of the vector directed at the Arg-108 residue, leading to the identification of highly potent 3-azabicyclo[3.1.0]hexane acetic acid-based KHK inhibitors by combined use of parallel medicinal chemistry and structure-based drug design. Discovery of PF-06835919: A Potent Inhibitor of Ketohexokinase (KHK) for the Treatment of Metabolic Disorders Driven by the Overconsumption of Fructose.,Futatsugi K, Smith AC, Tu M, Raymer B, Ahn K, Coffey SB, Dowling MS, Fernando DP, Gutierrez JA, Huard K, Jasti J, Kalgutkar AS, Knafels JD, Pandit J, Parris KD, Perez S, Pfefferkorn JA, Price DA, Ryder T, Shavnya A, Stock IA, Tsai AS, Tesz GJ, Thuma BA, Weng Y, Wisniewska HM, Xing G, Zhou J, Magee TV J Med Chem. 2020 Sep 27. doi: 10.1021/acs.jmedchem.0c00944. PMID:32910646[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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