4COD

Encoded library technology as a source of hits for the discovery and lead optimization of a potent and selective class of bactericidal direct inhibitors of Mycobacterium tuberculosis InhA

4COD の概要

• エントリーDOI: 10.2210/pdb4cod/pdb
• 分子名称: ENOYL-[ACYL-CARRIER-PROTEIN] REDUCTASE [NADH], N-((3R,5S)-1-(benzofuran-3-carbonyl)-5-(ethylcarbamoyl)pyrrolidin-3-yl)-3-ethyl-1-methyl-1H-pyrazole-5-carboxamide, NICOTINAMIDE-ADENINE-DINUCLEOTIDE, ... (4 entities in total)
• 機能のキーワード: transferase, elt, encoded library technology, isoniazid, l-proline
• 由来する生物種: MYCOBACTERIUM TUBERCULOSIS
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 118622.79

構造登録者

Encinas, L.,OKeefe, H.,Neu, M.,Convery, M.A.,McDowell, W.,Mendoza-Losana, A.,Pages, L.B.,Castro-Pichel, J.,Evindar, G. (登録日: 2014-01-28, 公開日: 2014-02-12, 最終更新日: 2023-12-20)

主引用文献

Encinas, L.,O'Keefe, H.,Neu, M.,Remuinan, M.J.,Patel, A.M.,Guardia, A.,Davie, C.P.,Perez-Macias, N.,Yang, H.,Convery, M.A.,Messer, J.A.,Perez-Herran, E.,Centrella, P.A.,Alvarez-Gomez, D.,Clark, M.A.,Huss, S.,O'Donovan, G.K.,Ortega-Muro, F.,Mcdowell, W.,Castaneda, P.,Arico-Muendel, C.C.,Pajk, S.,Rullas, J.,Angulo-Barturen, I.,Alvarez-Ruiz, E.,Mendoza-Losana, A.,Pages, L.B.,Castro-Pichel, J.,Evindar, G.
Encoded Library Technology as a Source of Hits for the Discovery and Lead Optimization of a Potent and Selective Class of Bactericidal Direct Inhibitors of Mycobacterium Tuberculosis Inha.
J.Med.Chem., 57:1276-, 2014

PubMed Abstract: Tuberculosis (TB) is one of the world's oldest and deadliest diseases, killing a person every 20 s. InhA, the enoyl-ACP reductase from Mycobacterium tuberculosis, is the target of the frontline antitubercular drug isoniazid (INH). Compounds that directly target InhA and do not require activation by mycobacterial catalase peroxidase KatG are promising candidates for treating infections caused by INH resistant strains. The application of the encoded library technology (ELT) to the discovery of direct InhA inhibitors yielded compound 7 endowed with good enzymatic potency but with low antitubercular potency. This work reports the hit identification, the selected strategy for potency optimization, the structure-activity relationships of a hundred analogues synthesized, and the results of the in vivo efficacy studies performed with the lead compound 65.

PubMed: 24450589
DOI: 10.1021/JM401326J

実験手法

X-RAY DIFFRACTION (2.4 Å)