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

spinqualitylabelsall models 4cod, resolution 2.40Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4cod is a 4 chain structure with sequence from "bacillus_tuberculosis"_(zopf_1883)_klein_1884 "bacillus tuberculosis" (zopf 1883) klein 1884. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: KV1, NAD Activity: [acyl-carrier-protein_reductase_(NADH) Enoyl-[acyl-carrier-protein] reductase (NADH)], with EC number 1.3.1.9 Resources: FirstGlance, OCA, RCSB, PDBsum Publication Abstract from PubMed 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. 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.,Encinas L, O'Keefe H, Neu M, Remuinan MJ, Patel AM, Guardia A, Davie CP, Perez-Macias N, Yang H, Convery MA, Messer JA, Perez-Herran E, Centrella PA, Alvarez-Gomez D, Clark MA, Huss S, O'Donovan GK, Ortega-Muro F, McDowell W, Castaneda P, Arico-Muendel CC, Pajk S, Rullas J, Angulo-Barturen I, Alvarez-Ruiz E, Mendoza-Losana A, Ballell Pages L, Castro-Pichel J, Evindar G J Med Chem. 2014 Feb 5. PMID:24450589 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Enoyl-Acyl-Carrier Protein Reductase

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