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

International Journal of Molecular Sciences
Camilo Henrique da Silva LimaMagaly Girão Albuquerque

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...Continue Reading

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Citations

Dec 14, 2016·Medicinal Research Reviews·Sergio M MarquesJiri Damborsky
Nov 3, 2016·Archiv der Pharmazie·Bharathkumar InturiMadhusudhan N Purohit
Dec 4, 2019·European Journal of Medicinal Chemistry·Francisco do Vale Chaves E MelloIsrael Felzenszwalb

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Methods Mentioned

BETA
X-ray
isothermal titration calorimetry

Software Mentioned

GROMACS
MVD
AnteChamber PYthon Parcer InterfacE ( ACPYPE )
hbmap2grace
Molegro Virtual Docker ( MVD )
MolDock
Spartan
ANTECHAMBER
ACPYPE
MKTOP

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