8OTL

structure of InhA from Mycobacterium tuberculosis in complex with 5-(((4-(2-hydroxyphenoxy)benzyl)(octyl)amino)methyl)-2-phenoxyphenol

8OTL の概要

• エントリーDOI: 10.2210/pdb8otl/pdb
• 分子名称: Enoyl-[acyl-carrier-protein] reductase [NADH], NICOTINAMIDE-ADENINE-DINUCLEOTIDE, ACETATE ION, ... (6 entities in total)
• 機能のキーワード: enoyl-acp-reductase type ii fatty acid synthase mycolic acids tuberculosis therapeutic target, oxidoreductase
• 由来する生物種: Mycobacterium tuberculosis
• タンパク質・核酸の鎖数: 6
• 化学式量合計: 177770.79

構造登録者

Tamhaev, R.,Maveyraud, L.,Chebaiki, M.,Lherbet, C.,Mourey, L. (登録日: 2023-04-21, 公開日: 2024-01-24)

主引用文献

Tamhaev, R.,Grosjean, E.,Ahamed, H.,Chebaiki, M.,Rodriguez, F.,Recchia, D.,Degiacomi, G.,Pasca, M.R.,Maveyraud, L.,Mourey, L.,Lherbet, C.
Exploring the plasticity of the InhA substrate-binding site using new diaryl ether inhibitors.
Bioorg.Chem., 143:107032-107032, 2023

PubMed Abstract: Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), remains a worldwide scourge with more than 10 million people affected yearly. Among the proteins essential for the survival of Mtb, InhA has been and is still clinically validated as a therapeutic target. A new family of direct diaryl ether inhibitors, not requiring prior activation by the catalase peroxidase enzyme KatG, has been designed with the ambition of fully occupying the InhA substrate-binding site. Thus, eleven compounds, featuring three pharmacophores within the same molecule, were synthesized. One of them, 5-(((4-(2-hydroxyphenoxy)benzyl)(octyl)amino)methyl)-2-phenoxyphenol (compound 21), showed good inhibitory activity against InhA with IC of 0.70 µM. The crystal structure of compound 21 in complex with InhA/NAD showed how the molecule fills the substrate-binding site as well as the minor portal of InhA. This study represents a further step towards the design of new inhibitors of InhA.

PubMed: 38128204
DOI: 10.1016/j.bioorg.2023.107032

実験手法

X-RAY DIFFRACTION (2.108 Å)