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==Mycobacterium tuberculosis dihydrofolate reductase in complex with 4-(3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-4-oxobutanoic acid(fragment 16)== | ==Mycobacterium tuberculosis dihydrofolate reductase in complex with 4-(3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-4-oxobutanoic acid(fragment 16)== | ||
<StructureSection load='6vsf' size='340' side='right'caption='[[6vsf]]' scene=''> | <StructureSection load='6vsf' size='340' side='right'caption='[[6vsf]], [[Resolution|resolution]] 2.01Å' 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=6VSF OCA]. For a <b>guided tour on the structure components</b> use [ | <table><tr><td colspan='2'>[[6vsf]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Mycobacterium_tuberculosis_H37Rv Mycobacterium tuberculosis H37Rv]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6VSF OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6VSF 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]] 2.012Å</td></tr> | ||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CO:COBALT+(II)+ION'>CO</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=NAP:NADP+NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NAP</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</scene>, <scene name='pdbligand=RKY:4-(3,4-dihydro-2H-1,5-benzodioxepin-7-yl)-4-oxobutanoic+acid'>RKY</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=6vsf FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6vsf OCA], [https://pdbe.org/6vsf PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6vsf RCSB], [https://www.ebi.ac.uk/pdbsum/6vsf PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6vsf ProSAT]</span></td></tr> | |||
</table> | </table> | ||
== Function == | |||
[https://www.uniprot.org/uniprot/DYR_MYCTU DYR_MYCTU] Key enzyme in folate metabolism. Catalyzes an essential reaction for de novo glycine and purine synthesis, and for DNA precursor synthesis. | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Dihydrofolate reductase (DHFR), a key enzyme involved in folate metabolism, is a widely explored target in the treatment of cancer, immune diseases, bacteria, and protozoa infections. Although several antifolates have proved successful in the treatment of infectious diseases, they have been underexplored to combat tuberculosis, despite the essentiality of M. tuberculosis DHFR (MtDHFR). Herein, we describe an integrated fragment-based drug discovery approach to target MtDHFR that has identified hits with scaffolds not yet explored in any previous drug design campaign for this enzyme. The application of a SAR by catalog strategy of an in house library for one of the identified fragments has led to a series of molecules that bind to MtDHFR with low micromolar affinities. Crystal structures of MtDHFR in complex with compounds of this series demonstrated a novel binding mode that considerably differs from other DHFR antifolates, thus opening perspectives for the development of relevant MtDHFR inhibitors. | |||
Using a Fragment-Based Approach to Identify Alternative Chemical Scaffolds Targeting Dihydrofolate Reductase from Mycobacterium tuberculosis.,Ribeiro JA, Hammer A, Libreros-Zuniga GA, Chavez-Pacheco SM, Tyrakis P, de Oliveira GS, Kirkman T, El Bakali J, Rocco SA, Sforca ML, Parise-Filho R, Coyne AG, Blundell TL, Abell C, Dias MVB ACS Infect Dis. 2020 Aug 14;6(8):2192-2201. doi: 10.1021/acsinfecdis.0c00263., Epub 2020 Jul 10. PMID:32603583<ref>PMID:32603583</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 6vsf" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[Dihydrofolate reductase 3D structures|Dihydrofolate reductase 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Mycobacterium tuberculosis H37Rv]] | |||
[[Category: Dias MVB]] | [[Category: Dias MVB]] | ||
[[Category: Ribeiro JA]] | [[Category: Ribeiro JA]] | ||
Latest revision as of 11:18, 11 October 2023
Mycobacterium tuberculosis dihydrofolate reductase in complex with 4-(3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-4-oxobutanoic acid(fragment 16)Mycobacterium tuberculosis dihydrofolate reductase in complex with 4-(3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-4-oxobutanoic acid(fragment 16)
Structural highlights
FunctionDYR_MYCTU Key enzyme in folate metabolism. Catalyzes an essential reaction for de novo glycine and purine synthesis, and for DNA precursor synthesis. Publication Abstract from PubMedDihydrofolate reductase (DHFR), a key enzyme involved in folate metabolism, is a widely explored target in the treatment of cancer, immune diseases, bacteria, and protozoa infections. Although several antifolates have proved successful in the treatment of infectious diseases, they have been underexplored to combat tuberculosis, despite the essentiality of M. tuberculosis DHFR (MtDHFR). Herein, we describe an integrated fragment-based drug discovery approach to target MtDHFR that has identified hits with scaffolds not yet explored in any previous drug design campaign for this enzyme. The application of a SAR by catalog strategy of an in house library for one of the identified fragments has led to a series of molecules that bind to MtDHFR with low micromolar affinities. Crystal structures of MtDHFR in complex with compounds of this series demonstrated a novel binding mode that considerably differs from other DHFR antifolates, thus opening perspectives for the development of relevant MtDHFR inhibitors. Using a Fragment-Based Approach to Identify Alternative Chemical Scaffolds Targeting Dihydrofolate Reductase from Mycobacterium tuberculosis.,Ribeiro JA, Hammer A, Libreros-Zuniga GA, Chavez-Pacheco SM, Tyrakis P, de Oliveira GS, Kirkman T, El Bakali J, Rocco SA, Sforca ML, Parise-Filho R, Coyne AG, Blundell TL, Abell C, Dias MVB ACS Infect Dis. 2020 Aug 14;6(8):2192-2201. doi: 10.1021/acsinfecdis.0c00263., Epub 2020 Jul 10. PMID:32603583[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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