4J1N

Crystal structures of FabI from F. tularensis in complex with novel inhibitors based on the benzimidazole scaffold

4J1N の概要

• エントリーDOI: 10.2210/pdb4j1n/pdb
• 関連するPDBエントリー: 3UIC 4J3F 4J4T
• 分子名称: Enoyl-[acyl-carrier-protein] reductase [NADH], NICOTINAMIDE-ADENINE-DINUCLEOTIDE, 1-(4-methoxy-3-methylbenzyl)-1,5,6,7-tetrahydroindeno[5,6-d]imidazole, ... (5 entities in total)
• 機能のキーワード: rossmann fold, reductase, nadh, reduction, oxidoreductase-oxidoreductase inhibitor complex, oxidoreductase/oxidoreductase inhibitor
• 由来する生物種: Francisella tularensis subsp. tularensis
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 62016.82

構造登録者

Mehboob, S.,Boci, T.,Brubaker, L.,Santarsiero, B.D.,Johnson, M.E. (登録日: 2013-02-01, 公開日: 2014-07-23, 最終更新日: 2023-09-20)

主引用文献

Mehboob, S.,Song, J.,Hevener, K.E.,Su, P.C.,Boci, T.,Brubaker, L.,Truong, L.,Mistry, T.,Deng, J.,Cook, J.L.,Santarsiero, B.D.,Ghosh, A.K.,Johnson, M.E.
Structural and biological evaluation of a novel series of benzimidazole inhibitors of Francisella tularensis enoyl-ACP reductase (FabI).
Bioorg.Med.Chem.Lett., 25:1292-1296, 2015

PubMed Abstract: Francisella tularensis, the causative agent of tularemia, presents a significant biological threat and is a Category A priority pathogen due to its potential for weaponization. The bacterial FASII pathway is a viable target for the development of novel antibacterial agents treating Gram-negative infections. Here we report the advancement of a promising series of benzimidazole FabI (enoyl-ACP reductase) inhibitors to a second-generation using a systematic, structure-guided lead optimization strategy, and the determination of several co-crystal structures that confirm the binding mode of designed inhibitors. These compounds display an improved low nanomolar enzymatic activity as well as promising low microgram/mL antibacterial activity against both F. tularensis and Staphylococcus aureus and its methicillin-resistant strain (MRSA). The improvements in activity accompanying structural modifications lead to a better understanding of the relationship between the chemical structure and biological activity that encompasses both enzymatic and whole-cell activity.

PubMed: 25677657
DOI: 10.1016/j.bmcl.2015.01.048

実験手法

X-RAY DIFFRACTION (2.45 Å)