6q0d: Difference between revisions
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==CRYSTAL STRUCTURE OF LDHA IN COMPLEX WITH COMPOUND NCGC00384414-01 AT 2.05 A RESOLUTION== | ==CRYSTAL STRUCTURE OF LDHA IN COMPLEX WITH COMPOUND NCGC00384414-01 AT 2.05 A RESOLUTION== | ||
<StructureSection load='6q0d' size='340' side='right'caption='[[6q0d]]' scene=''> | <StructureSection load='6q0d' size='340' side='right'caption='[[6q0d]], [[Resolution|resolution]] 2.05Å' 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=6Q0D OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6Q0D FirstGlance]. <br> | <table><tr><td colspan='2'>[[6q0d]] is a 6 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6Q0D OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6Q0D FirstGlance]. <br> | ||
</td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=6q0d FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6q0d OCA], [http://pdbe.org/6q0d PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6q0d RCSB], [http://www.ebi.ac.uk/pdbsum/6q0d PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6q0d ProSAT]</span></td></tr> | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=NAI:1,4-DIHYDRONICOTINAMIDE+ADENINE+DINUCLEOTIDE'>NAI</scene>, <scene name='pdbligand=P8M:2-{3-[3-(cyclopentylethynyl)-4-fluorophenyl]-5-(cyclopropylmethyl)-4-[(3-fluoro-4-sulfamoylphenyl)methyl]-1H-pyrazol-1-yl}-1,3-thiazole-4-carboxylic+acid'>P8M</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</scene></td></tr> | ||
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">LDHA, PIG19 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr> | |||
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/L-lactate_dehydrogenase L-lactate dehydrogenase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.1.1.27 1.1.1.27] </span></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=6q0d FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6q0d OCA], [http://pdbe.org/6q0d PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6q0d RCSB], [http://www.ebi.ac.uk/pdbsum/6q0d PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6q0d ProSAT]</span></td></tr> | |||
</table> | </table> | ||
== Disease == | |||
[[http://www.uniprot.org/uniprot/LDHA_HUMAN LDHA_HUMAN]] Defects in LDHA are the cause of glycogen storage disease type 11 (GSD11) [MIM:[http://omim.org/entry/612933 612933]]. A metabolic disorder that results in exertional myoglobinuria, pain, cramps and easy fatigue.<ref>PMID:2334430</ref> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Lactate dehydrogenase (LDH) catalyzes the conversion of pyruvate to lactate, with concomitant oxidation of NADH as the final step in the glycolytic pathway. Glycolysis plays an important role in the metabolic plasticity of cancer cells and has long been recognized as a potential therapeutic target. Thus, potent, selective inhibitors of LDH represent an attractive therapeutic approach. However, to date, pharmacological agents have failed to achieve significant target engagement in vivo, possibly because the protein is present in cells at very high concentrations. We report herein a lead optimization campaign focused on a pyrazole-based series of compounds, using structure-based design concepts, coupled with optimization of cellular potency, in vitro drug-target residence times, and in vivo PK properties, to identify first-in-class inhibitors that demonstrate LDH inhibition in vivo. The lead compounds, named NCATS-SM1440 (43) and NCATS-SM1441 (52) possess desirable attributes for further studying the effect of in vivo LDH inhibition. . | |||
Pyrazole-Based Lactate Dehydrogenase (LDH) Inhibitors with Optimized Cell Activity and Pharmacokinetic Properties.,Rai G, Urban DJ, Mott BT, Hu X, Yang SM, Benavides GA, Johnson MS, Squadrito GL, Brimacombe KR, Lee TD, Cheff DM, Zhu H, Henderson MJ, Pohida K, Sulikowski GA, Dranow DM, Kabir M, Shah P, Padilha E, Tao D, Fang Y, Christov PP, Kim K, Jana S, Muttil P, Anderson T, Kunda NK, Hathaway HJ, Kusewitt DF, Oshima N, Cherukuri M, Davies DR, Norenberg JP, Sklar LA, Moore WJ, Dang CV, Stott GM, Neckers LM, Flint AJ, Usmar VD, Simeonov A, Waterson AG, Jadhav A, Hall MD, Maloney DJ J Med Chem. 2020 Sep 9. doi: 10.1021/acs.jmedchem.0c00916. PMID:32902275<ref>PMID:32902275</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 6q0d" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Human]] | |||
[[Category: L-lactate dehydrogenase]] | |||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Davies | [[Category: Davies, D R]] | ||
[[Category: Dranow | [[Category: Dranow, D M]] | ||
[[Category: Ldha]] | |||
[[Category: Oxidoreductase-oxidoreductase inhibitor complex]] | |||
Revision as of 09:33, 7 October 2020
CRYSTAL STRUCTURE OF LDHA IN COMPLEX WITH COMPOUND NCGC00384414-01 AT 2.05 A RESOLUTIONCRYSTAL STRUCTURE OF LDHA IN COMPLEX WITH COMPOUND NCGC00384414-01 AT 2.05 A RESOLUTION
Structural highlights
Disease[LDHA_HUMAN] Defects in LDHA are the cause of glycogen storage disease type 11 (GSD11) [MIM:612933]. A metabolic disorder that results in exertional myoglobinuria, pain, cramps and easy fatigue.[1] Publication Abstract from PubMedLactate dehydrogenase (LDH) catalyzes the conversion of pyruvate to lactate, with concomitant oxidation of NADH as the final step in the glycolytic pathway. Glycolysis plays an important role in the metabolic plasticity of cancer cells and has long been recognized as a potential therapeutic target. Thus, potent, selective inhibitors of LDH represent an attractive therapeutic approach. However, to date, pharmacological agents have failed to achieve significant target engagement in vivo, possibly because the protein is present in cells at very high concentrations. We report herein a lead optimization campaign focused on a pyrazole-based series of compounds, using structure-based design concepts, coupled with optimization of cellular potency, in vitro drug-target residence times, and in vivo PK properties, to identify first-in-class inhibitors that demonstrate LDH inhibition in vivo. The lead compounds, named NCATS-SM1440 (43) and NCATS-SM1441 (52) possess desirable attributes for further studying the effect of in vivo LDH inhibition. . Pyrazole-Based Lactate Dehydrogenase (LDH) Inhibitors with Optimized Cell Activity and Pharmacokinetic Properties.,Rai G, Urban DJ, Mott BT, Hu X, Yang SM, Benavides GA, Johnson MS, Squadrito GL, Brimacombe KR, Lee TD, Cheff DM, Zhu H, Henderson MJ, Pohida K, Sulikowski GA, Dranow DM, Kabir M, Shah P, Padilha E, Tao D, Fang Y, Christov PP, Kim K, Jana S, Muttil P, Anderson T, Kunda NK, Hathaway HJ, Kusewitt DF, Oshima N, Cherukuri M, Davies DR, Norenberg JP, Sklar LA, Moore WJ, Dang CV, Stott GM, Neckers LM, Flint AJ, Usmar VD, Simeonov A, Waterson AG, Jadhav A, Hall MD, Maloney DJ J Med Chem. 2020 Sep 9. doi: 10.1021/acs.jmedchem.0c00916. PMID:32902275[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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