2NSD

Enoyl acyl carrier protein reductase InhA in complex with N-(4-methylbenzoyl)-4-benzylpiperidine

Summary for 2NSD

• Entry DOI: 10.2210/pdb2nsd/pdb
• Related: 1P45 2H7I 2H7L 2H7M 2H7N 2H7P
• Descriptor: Enoyl-[acyl-carrier-protein] reductase, NICOTINAMIDE-ADENINE-DINUCLEOTIDE, N-(4-METHYLBENZOYL)-4-BENZYLPIPERIDINE, ... (4 entities in total)
• Functional Keywords: oxidoreductase, inha, enoyl acyl carrier reductase, n-(4-methylbenzoyl)-4-benzylpiperidine
• Biological source: Mycobacterium tuberculosis H37Rv
• Total number of polymer chains: 2
• Total formula weight: 59023.22

Authors

He, X.,Alian, A.,Ortiz de Montellano, P.R. (deposition date: 2006-11-03, release date: 2007-09-18, Last modification date: 2023-08-30)

Primary citation

He, X.,Alian, A.,Ortiz de Montellano, P.R.
Inhibition of the Mycobacterium tuberculosis enoyl acyl carrier protein reductase InhA by arylamides.
Bioorg.Med.Chem., 15:6649-6658, 2007

PubMed Abstract: InhA, the enoyl acyl carrier protein reductase (ENR) from Mycobacterium tuberculosis, is one of the key enzymes involved in the type II fatty acid biosynthesis pathway of M. tuberculosis. We report here the discovery, through high-throughput screening, of a series of arylamides as a novel class of potent InhA inhibitors. These direct InhA inhibitors require no mycobacterial enzymatic activation and thus circumvent the resistance mechanism to antitubercular prodrugs such as INH and ETA that is most commonly observed in drug-resistant clinical isolates. The crystal structure of InhA complexed with one representative inhibitor reveals the binding mode of the inhibitor within the InhA active site. Further optimization through a microtiter synthesis strategy followed by in situ activity screening led to the discovery of a potent InhA inhibitor with in vitro IC(50)=90 nM, representing a 34-fold potency improvement over the lead compound.

PubMed: 17723305
DOI: 10.1016/j.bmc.2007.08.013

Experimental method

X-RAY DIFFRACTION (1.9 Å)