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

  • Pharit Kamsri
  • Auradee Punkvang
  • Patchareenart Saparpakorn
  • Supa Hannongbua
  • Stephan Irle
  • Pornpan Pungpo
Original Paper
Part of the following topical collections:
  1. Topical Collection 9th European Conference on Computational Chemistry (EuCo-CC9)

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.

Figure

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

Keywords

M. tuberculosis InhA 3D-QSAR MD simulation Diphenyl ether inhibitors 

Supplementary material

894_2014_2319_MOESM1_ESM.doc (696 kb)
ESM 1(DOC 695 kb)

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Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Pharit Kamsri
    • 1
  • Auradee Punkvang
    • 2
  • Patchareenart Saparpakorn
    • 3
  • Supa Hannongbua
    • 3
  • Stephan Irle
    • 4
  • Pornpan Pungpo
    • 1
  1. 1.Department of Chemistry, Faculty of ScienceUbon Ratchathani UniversityUbonratchathaniThailand
  2. 2.Faculty of Liberal Arts and Sciences, Division of ScienceNakhon Phanom UniversityNakhon PhanomThailand
  3. 3.Department of Chemistry, Faculty of ScienceKasetsart UniversityChatuchakThailand
  4. 4.Institute of Transformative Bio-Molecules (WPI-ITbM) and Department of Chemistry, Graduate School of ScienceNagoya UniversityNagoyaJapan

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