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Elucidating the structural basis of diphenyl ether derivatives as highly potent enoyl-ACP reductase inhibitors through molecular dynamics simulations and 3D-QSAR study

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Abstract

Diphenyl ether derivatives are good candidates for anti-tuberculosis agents that display a promising potency for inhibition of InhA, an essential enoyl-acyl carrier protein (ACP) reductase involved in fatty acid biosynthesis pathways in Mycobacterium tuberculosis. In this work, key structural features for the inhibition were identified by 3D-QSAR CoMSIA models, constructed based on available experimental binding properties of diphenyl ether inhibitors, and a set of four representative compounds was subjected to MD simulations of inhibitor-InhA complexes for the calculation of binding free energies. The results show that bulky groups are required for the R1 substituent on the phenyl A ring of the inhibitors to favor a hydrophobic pocket formed by residues Phe149, Met155, Pro156, Ala157, Tyr158, Pro193, Met199, Val203, Leu207, Ile215, and Leu218. Small substituents with a hydrophilic property are required at the R3 and R4 positions of the inhibitor phenyl B rings to form hydrogen bonds with the backbones of Gly96 and Met98, respectively. For the R2 substituent, small substituents with simultaneous hydrophilic or hydrophobic properties are required to favor the interaction with the pyrophosphate moiety of NAD+ and the methyl side chain of Ala198, respectively. The reported data provide structural guidance for the design of new and potent diphenyl ether-based inhibitors with high inhibitory activities against M. tuberculosis InhA.

The superimposition of compounds 17 (stick in cyan color), 18 (stick in yellow color), 19 (stick in green color) and 29 (stick in pink color) in the InhA pocket obtained from MD simulation

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Acknowledgments

This research has been supported by the Thailand Research Fund (DBG5380006, MRG5680169, and RTA5380010), the National Research Council of Thailand and Higher Education Research Promotion. The financial support from Royal Golden Jubilee Ph.D. Program (PHD/004/2554) to P. Kamsri is gratefully acknowledged. Faculty of Science, Ubon Ratchathani University, University of Vienna, ASEA-Uninet (Austrian - South-East Asian University Partnership Network), NECTEC (National Electronics and Computer Technology Center) and BIOTEC (National center for genetic engineering and biotechnology) are gratefully acknowledged for supporting this research.

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Authors and Affiliations

  1. Department of Chemistry, Faculty of Science, Ubon Ratchathani University, 85 Sthollmark Rd., Warinchamrap, Ubonratchathani, 34190, Thailand

    Pharit Kamsri & Pornpan Pungpo

  2. Faculty of Liberal Arts and Sciences, Division of Science, Nakhon Phanom University, Nakhon Phanom, 48000, Thailand

    Auradee Punkvang

  3. Department of Chemistry, Faculty of Science, Kasetsart University, Chatuchak, Bangkok, 10900, Thailand

    Patchareenart Saparpakorn & Supa Hannongbua

  4. Institute of Transformative Bio-Molecules (WPI-ITbM) and Department of Chemistry, Graduate School of Science, Nagoya University, Furo-cho, Chikusa-ku, Nagoya, 464-8602, Japan

    Stephan Irle

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  1. Pharit Kamsri
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This paper belongs to Topical Collection 9th European Conference on Computational Chemistry (EuCo-CC9)

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Kamsri, P., Punkvang, A., Saparpakorn, P. et al. Elucidating the structural basis of diphenyl ether derivatives as highly potent enoyl-ACP reductase inhibitors through molecular dynamics simulations and 3D-QSAR study. J Mol Model 20, 2319 (2014). https://doi.org/10.1007/s00894-014-2319-0

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