6VVB
Mycobacterium tuberculosis dihydrofolate reductase in complex with 6-methyl-5-(4-phenylthiazol-2-yl)-2- (trifluoromethyl)nicotinic acid (fragment 10)
Summary for 6VVB
| Entry DOI | 10.2210/pdb6vvb/pdb |
| Descriptor | Dihydrofolate reductase, 6-methyl-5-(4-phenyl-1,3-thiazol-2-yl)-2-(trifluoromethyl)pyridine-3-carboxylic acid, 3,6,9,12,15,18-HEXAOXAICOSANE-1,20-DIOL, ... (5 entities in total) |
| Functional Keywords | folate pathway, oxidoreductase |
| Biological source | Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv) |
| Total number of polymer chains | 1 |
| Total formula weight | 19327.42 |
| Authors | Tyrakis, P.,Dias, M.V.B. (deposition date: 2020-02-17, release date: 2020-07-15, Last modification date: 2023-10-11) |
| Primary citation | Ribeiro, J.A.,Hammer, A.,Libreros-Zuniga, G.A.,Chavez-Pacheco, S.M.,Tyrakis, P.,de Oliveira, G.S.,Kirkman, T.,El Bakali, J.,Rocco, S.A.,Sforca, M.L.,Parise-Filho, R.,Coyne, A.G.,Blundell, T.L.,Abell, C.,Dias, M.V.B. Using a Fragment-Based Approach to Identify Alternative Chemical Scaffolds Targeting Dihydrofolate Reductase fromMycobacterium tuberculosis. Acs Infect Dis., 6:2192-2201, 2020 Cited by PubMed Abstract: 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 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. PubMed: 32603583DOI: 10.1021/acsinfecdis.0c00263 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.45 Å) |
Structure validation
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