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

Summary for 4COD

• Entry DOI: 10.2210/pdb4cod/pdb
• Descriptor: 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)
• Functional Keywords: transferase, elt, encoded library technology, isoniazid, l-proline
• Biological source: MYCOBACTERIUM TUBERCULOSIS
• Total number of polymer chains: 4
• Total formula weight: 118622.79

Authors

Encinas, L.,OKeefe, H.,Neu, M.,Convery, M.A.,McDowell, W.,Mendoza-Losana, A.,Pages, L.B.,Castro-Pichel, J.,Evindar, G. (deposition date: 2014-01-28, release date: 2014-02-12, Last modification date: 2023-12-20)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.4 Å)