6HRW

EthR2 in complex with compound 1 (BDM14272)

6HRW の概要

• エントリーDOI: 10.2210/pdb6hrw/pdb
• 分子名称: Probable transcriptional regulatory protein, (1~{S},5~{R})-8-[2-(4-chlorophenyl)ethyl]-8-azabicyclo[3.2.1]octan-3-one (3 entities in total)
• 機能のキーワード: helix-turn-helix, tetr-family, complex, inhibitor, drug design, tuberculosis, ethionamide, dna binding protein
• 由来する生物種: Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 48508.90

構造登録者

Wintjens, R.,Wohlkonig, A.,Tanina, A. (登録日: 2018-09-28, 公開日: 2019-02-27, 最終更新日: 2024-01-24)

主引用文献

Prevet, H.,Moune, M.,Tanina, A.,Kemmer, C.,Herledan, A.,Frita, R.,Wohlkonig, A.,Bourotte, M.,Villemagne, B.,Leroux, F.,Gitzinger, M.,Baulard, A.R.,Deprez, B.,Wintjens, R.,Willand, N.,Flipo, M.
A fragment-based approach towards the discovery of N-substituted tropinones as inhibitors of Mycobacterium tuberculosis transcriptional regulator EthR2.
Eur J Med Chem, 167:426-438, 2019

PubMed Abstract: Tuberculosis (TB) caused by the pathogen Mycobacterium tuberculosis, represents one of the most challenging threat to public health worldwide, and with the increasing resistance to approved TB drugs, it is needed to develop new strategies to address this issue. Ethionamide is one of the most widely used drugs for the treatment of multidrug-resistant TB. It is a prodrug that requires activation by mycobacterial monooxygenases to inhibit the enoyl-ACP reductase InhA, which is involved in mycolic acid biosynthesis. Very recently, we identified that inhibition of a transcriptional repressor, termed EthR2, derepresses a new bioactivation pathway that results in the boosting of ethionamide activation. Herein, we describe the identification of potent EthR2 inhibitors using fragment-based screening and structure-based optimization. A target-based screening of a fragment library using thermal shift assay followed by X-ray crystallography identified 5 hits. Rapid optimization of the tropinone chemical series led to compounds with improved in vitro potency.

PubMed: 30784877
DOI: 10.1016/j.ejmech.2019.02.023

実験手法

X-RAY DIFFRACTION (2.45 Å)