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

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 Oct 7;16(10):23695-722. doi: 10.3390/ijms161023695.
Camilo Henrique da Silva Lima 1 2,  Ricardo Bicca de Alencastro 3,  Carlos Roland Kaiser 4,  Marcus Vinícius Nora de Souza 5 6,  Carlos Rangel Rodrigues 7,  Magaly Girão Albuquerque 8
Affiliations

Affiliations

  • 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. camilolima@iq.ufrj.br.
  • 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. camilolima@iq.ufrj.br.
  • 3 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. bicca@iq.ufrj.br.
  • 4 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. kaiser@iq.ufrj.br.
  • 5 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. marcos_souza@far.fiocruz.br.
  • 6 Oswaldo Cruz Foundation (Fundação Osvaldo Cruz, FioCruz), Institute of Pharmaceutical Technology (Instituto de Tecnologia em Fármacos, FarManguinhos), 21041-250 Rio de Janeiro, RJ, Brazil. marcos_souza@far.fiocruz.br.
  • 7 Graduate Program in Pharmaceutical Sciences, College of Pharmacy (Faculdade de Farmácia), Federal University of Rio de Janeiro, 21949-900 Rio de Janeiro, RJ, Brazil. rangel@pharma.ufrj.br.
  • 8 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. magaly@iq.ufrj.br.
PMID: 26457706 DOI: 10.3390/ijms161023695
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.

Keywords

Mycobacterium tuberculosis; diphenyl ethers inhibitors; enoyl-ACP reductase (InhA); molecular dynamics simulation; triclosan derivatives; water-bridge hydrogen bond.

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