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.
Highlights
Tuberculosis (TB) is an infecto-contagious disease caused by Mycobacterium tuberculosis (MTB), mainly affecting lungs, but it can infect others vital organs, such as central nervous, genitourinary, and osteoarticular systems [1,2,3]
In order to evaluate the main structural changes that lead to the inhibition of the NADH-dependent enoyl-acyl carrier protein (ACP) reductase enzyme from Mycobacterium tuberculosis (InhA), we carried out up to 20 or 40 ns of molecular dynamics (MD) simulations of 12 aqueous protein systems, using the GROMACS 4.5 package, by investigating one binary and 11 ternary complexes
In order to understand the structure-activity relationships (SAR) into the design of new and more potent anti-TB drugs, it was monitored the lifetime of the main intermolecular interactions in these systems: hydrogen bonds and hydrophobic contacts between protein and ligands
Summary
Tuberculosis (TB) is an infecto-contagious disease caused by Mycobacterium tuberculosis (MTB), mainly affecting lungs, but it can infect others vital organs, such as central nervous, genitourinary, and osteoarticular systems [1,2,3]. The anti-tuberculosis drug isoniazid acts as a pro-drug, activated by oxidation catalyzed by M. tuberculosis catalase-peroxidase (KatG) This product and cofactor (NADH or NAD+) react to form an adduct that inhibits InhA, disrupting the biosynthesis of mycolic acids (FAS-II), the main components of the mycobacterial cell wall, causing cell death [11]. Table 1), in ternary complexes with InhA and the oxidized cofactor form (NAD+), solved by X-ray diffraction and available in the Protein Data Bank (PDB; http://www.rcsb.org/pdb/) [22], allowed researchers to describe the main H-bonding and hydrophobic enzyme-inhibitor interactions in the substrate binding pocket [23,24]. The results obtained from this MD study could help to design new, more potent and effective InhA inhibitors in order to improve the pharmacological treatment against TB
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