4qxm | pdb_00004qxm

Crystal structure of the InhA:GSK_SB713 complex

spinqualitylabelsall models 4qxm, resolution 2.20Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4qxm is a 4 chain structure with sequence from Mycobacterium tuberculosis H37Rv. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.196Å Ligands: 713, NAD Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function INHA_MYCTU Publication Abstract from PubMed Isoniazid (INH) remains one of the cornerstones of antitubercular chemotherapy for drug-sensitive strains of M. tuberculosis bacteria. However, the increasing prevalence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains containing mutations in the KatG enzyme, which is responsible for the activation of INH into its antitubercular form, have rendered this drug of little or no use in many cases of drug-resistant tuberculosis. Presented herein is a novel family of antitubercular direct NADH-dependent 2-trans enoyl-acyl carrier protein reductase (InhA) inhibitors based on an N-benzyl-4-((heteroaryl)methyl)benzamide template; unlike INH, these do not require prior activation by KatG. Given their direct InhA target engagement, these compounds should be able to circumvent KatG-related resistance in the clinic. The lead molecules were shown to be potent inhibitors of InhA and showed activity against M. tuberculosis bacteria. This new family of inhibitors was found to be chemically tractable, as exemplified by the facile synthesis of analogues and the establishment of structure-activity relationships. Furthermore, a co-crystal structure of the initial hit with the enzyme is disclosed, providing valuable information toward the design of new InhA inhibitors for the treatment of MDR/XDR tuberculosis. N-Benzyl-4-((heteroaryl)methyl)benzamides: A New Class of Direct NADH-Dependent 2-trans Enoyl-Acyl Carrier Protein Reductase (InhA) Inhibitors with Antitubercular Activity.,Guardia A, Gulten G, Fernandez R, Gomez J, Wang F, Convery M, Blanco D, Martinez M, Perez-Herran E, Alonso M, Ortega F, Rullas J, Calvo D, Mata L, Young R, Sacchettini JC, Mendoza-Losana A, Remuinan M, Ballell Pages L, Castro-Pichel J ChemMedChem. 2016 Apr 5;11(7):687-701. doi: 10.1002/cmdc.201600020. Epub 2016 Mar, 2. PMID:26934341 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Enoyl-Acyl-Carrier Protein Reductase 3D structures

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