8u0q
From Proteopedia
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| - | '''Unreleased structure''' | ||
| - | + | ==Co-crystal structure of optimized analog TDI-13537 provided new insights into the potency determinants of the sulfonamide inhibitor series== | |
| + | <StructureSection load='8u0q' size='340' side='right'caption='[[8u0q]], [[Resolution|resolution]] 1.69Å' scene=''> | ||
| + | == Structural highlights == | ||
| + | <table><tr><td colspan='2'>[[8u0q]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Mycobacterium_tuberculosis Mycobacterium tuberculosis]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8U0Q OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8U0Q FirstGlance]. <br> | ||
| + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.69Å</td></tr> | ||
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=FAD:FLAVIN-ADENINE+DINUCLEOTIDE'>FAD</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=U4I:N-(3-acetamidophenyl)-N~2~-[3-(difluoromethyl)-5-methylbenzene-1-sulfonyl]-N~2~-methylglycinamide'>U4I</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=8u0q FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8u0q OCA], [https://pdbe.org/8u0q PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8u0q RCSB], [https://www.ebi.ac.uk/pdbsum/8u0q PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8u0q ProSAT]</span></td></tr> | ||
| + | </table> | ||
| + | == Function == | ||
| + | [https://www.uniprot.org/uniprot/DLDH_MYCTU DLDH_MYCTU] Lipoamide dehydrogenase is an essential component of the alpha-ketoacid dehydrogenase complexes, namely the pyruvate dehydrogenase (PDH) complex, the branched-chain alpha-ketoacid dehydrogenase (BCKADH) complex, and likely also the 2-oxoglutarate dehydrogenase (ODH) complex. Catalyzes the reoxidation of dihydrolipoyl groups which are covalently attached to the lipoate acyltransferase components (E2) of the complexes. Is also able to catalyze the transhydrogenation of NADH and thio-NAD(+) in the absence of D,L-lipoamide, and the NADH-dependent reduction of quinones in vitro.<ref>PMID:11560483</ref> <ref>PMID:11799204</ref> <ref>PMID:16045627</ref> <ref>PMID:21238944</ref> <ref>PMID:16093239</ref> Together with AhpC, AhpD and DlaT, Lpd constitutes an NADH-dependent peroxidase active against hydrogen and alkyl peroxides as well as serving as a peroxynitrite reductase, thus protecting the bacterium against reactive nitrogen intermediates and oxidative stress generated by the host immune system.<ref>PMID:11560483</ref> <ref>PMID:11799204</ref> <ref>PMID:16045627</ref> <ref>PMID:21238944</ref> <ref>PMID:16093239</ref> Appears to be essential for Mtb pathogenesis.<ref>PMID:11560483</ref> <ref>PMID:11799204</ref> <ref>PMID:16045627</ref> <ref>PMID:21238944</ref> <ref>PMID:16093239</ref> | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | Lpd (lipoamide dehydrogenase) in Mycobacterium tuberculosis (Mtb) is required for virulence and is a genetically validated tuberculosis (TB) target. Numerous screens have been performed over the last decade, yet only two inhibitor series have been identified. Recent advances in large-scale virtual screening methods combined with make-on-demand compound libraries have shown the potential for finding novel hits. In this study, the Enamine REAL library consisting of approximately 1.12 billion compounds was efficiently screened using the GPU Shape screen method against Mtb Lpd to find additional chemical matter that would expand on the known sulfonamide inhibitor series. We identified six new inhibitors with IC(50) in the range of 5-100 muM. While these compounds remained chemically close to the already known sulfonamide series inhibitors, some diversity was found in the cores of the hits. The two most potent hits were further validated by one-step potency optimization to submicromolar levels. The co-crystal structure of optimized analogue TDI-13537 provided new insights into the potency determinants of the series. | ||
| - | + | Shape-Based Virtual Screening of a Billion-Compound Library Identifies Mycobacterial Lipoamide Dehydrogenase Inhibitors.,Michino M, Beautrait A, Boyles NA, Nadupalli A, Dementiev A, Sun S, Ginn J, Baxt L, Suto R, Bryk R, Jerome SV, Huggins DJ, Vendome J ACS Bio Med Chem Au. 2023 Sep 8;3(6):507-515. doi: , 10.1021/acsbiomedchemau.3c00046. eCollection 2023 Dec 20. PMID:38144256<ref>PMID:38144256</ref> | |
| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| - | [[Category: | + | </div> |
| - | [[Category: Bryk | + | <div class="pdbe-citations 8u0q" style="background-color:#fffaf0;"></div> |
| - | [[Category: Dementiev | + | == References == |
| - | [[Category: Ginn | + | <references/> |
| - | [[Category: Michino | + | __TOC__ |
| - | [[Category: Olland | + | </StructureSection> |
| - | [[Category: Vendome | + | [[Category: Large Structures]] |
| + | [[Category: Mycobacterium tuberculosis]] | ||
| + | [[Category: Bryk R]] | ||
| + | [[Category: Dementiev AA]] | ||
| + | [[Category: Ginn J]] | ||
| + | [[Category: Michino M]] | ||
| + | [[Category: Olland A]] | ||
| + | [[Category: Vendome J]] | ||
Current revision
Co-crystal structure of optimized analog TDI-13537 provided new insights into the potency determinants of the sulfonamide inhibitor series
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