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Int. J. Mol. Sci. 2015, 16(10), 23695-23722; doi:10.3390/ijms161023695

Aqueous Molecular Dynamics Simulations of the M. tuberculosis Enoyl-ACP Reductase-NADH System and Its Complex with a Substrate Mimic or Diphenyl Ethers Inhibitors

1
Graduate Program in Chemistry, Institute of Chemistry (Instituto de Química), Federal University of Rio de Janeiro (Universidade Federal do Rio de Janeiro, UFRJ), 21949-900 Rio de Janeiro, RJ, Brazil
2
Oswaldo Cruz Foundation (Fundação Osvaldo Cruz, FioCruz), Institute of Pharmaceutical Technology (Instituto de Tecnologia em Fármacos, FarManguinhos), 21041-250 Rio de Janeiro, RJ, Brazil
3
Graduate Program in Pharmaceutical Sciences, College of Pharmacy (Faculdade de Farmácia), Federal University of Rio de Janeiro, 21949-900 Rio de Janeiro, RJ, Brazil
*
Authors to whom correspondence should be addressed.
Academic Editor: Malcolm D´Souza
Received: 1 July 2015 / Revised: 18 August 2015 / Accepted: 8 September 2015 / Published: 7 October 2015
(This article belongs to the Special Issue Solution Chemical Kinetics)
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Abstract

Molecular dynamics (MD) simulations of 12 aqueous systems of the NADH-dependent enoyl-ACP reductase from Mycobacterium tuberculosis (InhA) were carried out for up to 20–40 ns using the GROMACS 4.5 package. Simulations of the holoenzyme, holoenzyme-substrate, and 10 holoenzyme-inhibitor complexes were conducted in order to gain more insight about the secondary structure motifs of the InhA substrate-binding pocket. We monitored the lifetime of the main intermolecular interactions: hydrogen bonds and hydrophobic contacts. Our MD simulations demonstrate the importance of evaluating the conformational changes that occur close to the active site of the enzyme-cofactor complex before and after binding of the ligand and the influence of the water molecules. Moreover, the protein-inhibitor total steric (ELJ) and electrostatic (EC) interaction energies, related to Gly96 and Tyr158, are able to explain 80% of the biological response variance according to the best linear equation, pKi = 7.772 − 0.1885 × Gly96 + 0.0517 × Tyr158 (R2 = 0.80; n = 10), where interactions with Gly96, mainly electrostatic, increase the biological response, while those with Tyr158 decrease. These results will help to understand the structure-activity relationships and to design new and more potent anti-TB drugs. View Full-Text
Keywords: Mycobacterium tuberculosis; enoyl-ACP reductase (InhA); molecular dynamics simulation; diphenyl ethers inhibitors; triclosan derivatives; water-bridge hydrogen bond Mycobacterium tuberculosis; enoyl-ACP reductase (InhA); molecular dynamics simulation; diphenyl ethers inhibitors; triclosan derivatives; water-bridge hydrogen bond
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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Lima, C.H.S.; de Alencastro, R.B.; Kaiser, C.R.; de Souza, M.V.N.; Rodrigues, C.R.; Albuquerque, M.G. Aqueous Molecular Dynamics Simulations of the M. tuberculosis Enoyl-ACP Reductase-NADH System and Its Complex with a Substrate Mimic or Diphenyl Ethers Inhibitors. Int. J. Mol. Sci. 2015, 16, 23695-23722.

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