6y2j
Crystal structure of M. tuberculosis KasA in complex with 4,4,4-trifluoro-N-(isoquinolin-6-yl)butane-1-sulfonamideCrystal structure of M. tuberculosis KasA in complex with 4,4,4-trifluoro-N-(isoquinolin-6-yl)butane-1-sulfonamide
Structural highlights
Function[FAB1_MYCTU] Catalyzes the condensation reaction of fatty acid synthesis by the addition to an acyl acceptor of two carbons from malonyl-ACP (By similarity). Publication Abstract from PubMedIn the course of optimizing a novel indazole sulfonamide series that inhibits beta-ketoacyl-ACP synthase (KasA) of Mycobacterium tuberculosis, a mutagenic aniline metabolite was identified. Further lead optimization efforts were therefore dedicated to eliminating this critical liability by removing the embedded aniline moiety or modifying its steric or electronic environment. While the narrow SAR space against the target ultimately rendered this goal unsuccessful, key structural knowledge around the binding site of this underexplored target for TB was generated to inform future discovery efforts. Exploring the SAR of the beta-Ketoacyl-ACP Synthase Inhibitor GSK3011724A and Optimization around a Genotoxic Metabolite.,Cunningham F, Esquivias J, Fernandez-Menendez R, Perez A, Guardia A, Escribano J, Rivero C, Vimal M, Cacho M, de Dios-Anton P, Martinez-Martinez MS, Jimenez E, Huertas Valentin L, Rebollo-Lopez MJ, Lopez-Roman EM, Sousa-Morcuende V, Rullas J, Neu M, Chung CW, Bates RH ACS Infect Dis. 2020 Mar 20. doi: 10.1021/acsinfecdis.9b00493. PMID:32196311[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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