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Rational design of InhA inhibitors in the class of diphenyl ether derivatives as potential anti-tubercular agents using molecular dynamics simulations

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A series of diphenyl ether derivatives were developed and showed promising potency for inhibiting InhA, an essential enoyl acyl carrier protein reductase involved in mycolic acid biosynthesis, leading to the lysis of Mycobacterium tuberculosis. To understand the structural basis of diphenyl ether derivatives for designing more potent inhibitors, molecular dynamics (MD) simulations were performed. Based on the obtained results, the dynamic behaviour in terms of flexibility, binding free energy, binding energy decomposition, conformation, and the inhibitor–enzyme interaction of diphenyl ether inhibitors were elucidated. Phe149, Tyr158, Met161, Met199, Val203 and NAD+ are the key residues for binding of diphenyl ether inhibitors in the InhA binding pocket. Our results could provide the structural concept to design new diphenyl ether inhibitors with better enzyme inhibitory activity against M. tuberculosis InhA. The present work facilitates the design of new and potentially more effective anti-tuberculosis agents.
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Keywords: Anti-tuberculosis agents; Diphenyl ether derivatives; InhA inhibitors; MD simulations; MM-PBSA

Document Type: Research Article

Affiliations: 1: Department of Chemistry, Faculty of Science, Ubon Ratchathani University, Ubonratchathani, Thailand 2: Faculty of Liberal Arts and Sciences, Nakhon Phanom University, Nakhon Phanom, Thailand 3: Department of Chemistry, Faculty of Science, Kasetsart University, Bangkok, Thailand 4: Institute for Theoretical Chemistry, University of Vienna, Vienna, Austria 5: Department of Electrical and Computer Engineering Faculty of Engineering, Thammasat University, Phatumtani, Thailand 6: National Center for Genetic Engineering and Biotechnology (BIOTEC), National Science and Technology Development Agency, Pathumthani, Thailand

Publication date: June 3, 2014

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