title: Aqueous Molecular Dynamics Simulations of the M. tuberculosis Enoyl-ACP Reductase-NADH System and Its Complex with a Substrate Mimic or Diphenyl Ethers Inhibitors.
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.
authors.affiliation: 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.|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.
authors.forename: Camilo Henrique
authors.initials: CH
authors.lastname: da Silva Lima
authors.affiliation: 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.
authors.forename: Ricardo Bicca
authors.initials: RB
authors.lastname: de Alencastro
authors.affiliation: 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.
authors.forename: Carlos Roland
authors.initials: CR
authors.lastname: Kaiser
authors.affiliation: 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.|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.
authors.forename: Marcus Vinícius Nora
authors.initials: MV
authors.lastname: de Souza
authors.affiliation: 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.
authors.forename: Carlos Rangel
authors.initials: CR
authors.lastname: Rodrigues
authors.affiliation: 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.
authors.forename: Magaly Girão
authors.initials: MG
authors.lastname: Albuquerque
mesh_terms: D020816:Amino Acid Motifs; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D050753:Enoyl-(Acyl-Carrier-Protein) Reductase (NADH) / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D056004:Molecular Dynamics Simulation; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000201:enzymology*; D010647:Phenyl Ethers / Q000494:pharmacology*; D017434:Protein Structure, Tertiary; D013329:Structure-Activity Relationship; D013816:Thermodynamics
chemical_list: D001426:Bacterial Proteins; D010647:Phenyl Ethers; D050753:Enoyl-(Acyl-Carrier-Protein) Reductase (NADH)
keywords: Mycobacterium tuberculosis; diphenyl ethers inhibitors; enoyl-ACP reductase (InhA); molecular dynamics simulation; triclosan derivatives; water-bridge hydrogen bond