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: Camilo Henrique da Silva Lima, Ricardo Bicca de Alencastro, Carlos Roland Kaiser, Marcus Vinícius Nora de Souza, Carlos Rangel Rodrigues, Magaly Girão Albuquerque
• Journal: International journal of molecular sciences (Int J Mol Sci) Vol. 16 Issue 10 Pg. 23695-722 (Oct 07 2015) ISSN: 1422-0067 [Electronic] Switzerland
• PMID: 26457706 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Bacterial Proteins
• Phenyl Ethers
• Enoyl-(Acyl-Carrier-Protein) Reductase (NADH)

Topics

• Amino Acid Motifs
• Bacterial Proteins (antagonists & inhibitors, metabolism)
• Enoyl-(Acyl-Carrier-Protein) Reductase (NADH) (antagonists & inhibitors, metabolism)
• Hydrogen Bonding
• Hydrophobic and Hydrophilic Interactions
• Molecular Dynamics Simulation
• Mycobacterium tuberculosis (drug effects, enzymology)
• Phenyl Ethers (pharmacology)
• Protein Structure, Tertiary
• Structure-Activity Relationship
• Thermodynamics