4OIM

Crystal structure of Mycobacterium tuberculosis InhA in complex with inhibitor PT119 in 2.4 M acetate

Summary for 4OIM

• Entry DOI: 10.2210/pdb4oim/pdb
• Related: 4OHU
• Descriptor: Enoyl-[acyl-carrier-protein] reductase [NADH], NICOTINAMIDE-ADENINE-DINUCLEOTIDE, 2-(2-CYANOPHENOXY)-5-HEXYLPHENOL, ... (5 entities in total)
• Functional Keywords: inhibition, high-concentration acetate, slow-onset inhibition, substrate binding loop conformational heterogeneity, oxidoreductase-oxidoreductase inhibitor complex, oxidoreductase/oxidoreductase inhibitor
• Biological source: Mycobacterium tuberculosis
• Total number of polymer chains: 1
• Total formula weight: 32334.42

Authors

Li, H.J.,Pan, P.,Lai, C.T.,Liu, N.,Garcia-Diaz, M.,Simmerling, C.,Tonge, P.J. (deposition date: 2014-01-20, release date: 2014-04-23, Last modification date: 2023-09-20)

Primary citation

Pan, P.,Knudson, S.E.,Bommineni, G.R.,Li, H.J.,Lai, C.T.,Liu, N.,Garcia-Diaz, M.,Simmerling, C.,Patil, S.S.,Slayden, R.A.,Tonge, P.J.
Time-Dependent Diaryl Ether Inhibitors of InhA: Structure-Activity Relationship Studies of Enzyme Inhibition, Antibacterial Activity, and in vivo Efficacy.
Chemmedchem, 9:776-791, 2014

PubMed Abstract: The diaryl ethers are a novel class of antituberculosis drug candidates that inhibit InhA, the enoyl-ACP reductase involved in the fatty acid biosynthesis (FASII) pathway, and have antibacterial activity against both drug-sensitive and drug-resistant strains of Mycobacterium tuberculosis. In the present work, we demonstrate that two time-dependent B-ring modified diaryl ether InhA inhibitors have antibacterial activity in a mouse model of TB infection when delivered by intraperitoneal injection. We propose that the efficacy of these compounds is related to their residence time on the enzyme, and to identify structural features that modulate drug-target residence time in this system, we have explored the inhibition of InhA by a series of B-ring modified analogues. Seven ortho-substituted compounds were found to be time-dependent inhibitors of InhA, where the slow step leading to the final enzyme-inhibitor complex (EI*) is thought to correlate with closure and ordering of the InhA substrate binding loop. A detailed mechanistic understanding of the molecular basis for residence time in this system will facilitate the development of InhA inhibitors with improved in vivo activity.

PubMed: 24616444
DOI: 10.1002/cmdc.201300429

Experimental method

X-RAY DIFFRACTION (1.848 Å)