6VVB

Mycobacterium tuberculosis dihydrofolate reductase in complex with 6-methyl-5-(4-phenylthiazol-2-yl)-2- (trifluoromethyl)nicotinic acid (fragment 10)

6VVB の概要

• エントリーDOI: 10.2210/pdb6vvb/pdb
• 分子名称: 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)
• 機能のキーワード: folate pathway, oxidoreductase
• 由来する生物種: Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 19327.42

構造登録者

Tyrakis, P.,Dias, M.V.B. (登録日: 2020-02-17, 公開日: 2020-07-15, 最終更新日: 2023-10-11)

主引用文献

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

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: 32603583
DOI: 10.1021/acsinfecdis.0c00263

実験手法

X-RAY DIFFRACTION (1.45 Å)