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

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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 (E_LJ) and electrostatic (E_C) interaction energies, related to Gly96 and Tyr158, are able to explain 80% of the biological response variance according to the best linear equation, pK_i = 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.

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Keywords: Mycobacterium tuberculosis; enoyl-ACP reductase (InhA); molecular dynamics simulation; diphenyl ethers inhibitors; triclosan derivatives; water-bridge hydrogen bond Document Type: Research Article DOI: 10.3390/ijms161023695 Publication date: 7 de Outubro de 2015