4QXM

Crystal structure of the InhA:GSK_SB713 complex

Summary for 4QXM

• Entry DOI: 10.2210/pdb4qxm/pdb
• Related: 3oew
• Descriptor: Enoyl-[acyl-carrier-protein] reductase [NADH], NICOTINAMIDE-ADENINE-DINUCLEOTIDE, N-(2-chloro-4-fluorobenzyl)-4-[(3,5-dimethyl-1H-pyrazol-1-yl)methyl]benzamide, ... (4 entities in total)
• Functional Keywords: rossman fold, enoyl-acp reductase, nadh binding, oxidoreductase-oxidoreductase inhibitor complex, oxidoreductase/oxidoreductase inhibitor
• Biological source: Mycobacterium tuberculosis H37Rv
• Total number of polymer chains: 4
• Total formula weight: 117616.50

Authors

Gulten, G.,Sacchettini, J.C. (deposition date: 2014-07-21, release date: 2015-07-22, Last modification date: 2023-09-20)

Primary citation

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, J.C.,Mendoza-Losana, A.,Remuinan, M.,Ballell Pages, L.,Castro-Pichel, J.
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.
Chemmedchem, 11:687-701, 2016

PubMed Abstract: 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.

PubMed: 26934341
DOI: 10.1002/cmdc.201600020

Experimental method

X-RAY DIFFRACTION (2.196 Å)