In SilicoIdentification of Triclosan Derivatives as Potential Inhibitors of MutantMycobacterium tuberculosisInhA

Abstract

Enoyl acyl carrier protein reductase (InhA) is a crucial enzyme for the biosynthesis of mycolic acids which are major compartments of the Mycobacterium tuberculosis (Mtb) cell wall. Direct inhibition of InhA without activation by drug-NADH adduct has clinical utility to overcome drug resistance. We aimed at the in silico identification of triclosan derivatives with the potential inhibitory effect of S94A-InhA as a clinically important mutant form. Caver Web 1.0 server was used to analyze the ligand transport through access tunnels. Two macrocyclic triclosan derivatives ( 4 and 6) could be identified with more energy-favorable transfer routes toward the enzyme active site. Molecular dynamics (MD) simulations (50 ns) of the best-scored compounds revealed the stability of enzyme structure upon binding to 4 and 6. Compound 4 could better retain enzyme stability upon target binding. Results of intermolecular H-bond analysis indicated that both complexes were mediated through hydrophobic contacts. Declined solvent accessible surface area (SASA) for the apo and bound enzyme states indicated non-destabilizing behavior and no structural relaxation. Electrostatic and van der Waals interactions between triclosan derivatives and their surroundings were used to acquire binding free energies through the linear interaction energy (LIE) method based on MD simulations (Average [Formula: see text], [Formula: see text] kcal/mol and [Formula: see text] kcal/mol). Both of the triclosan derivatives showed relatively stable energy variations and their steady accommodation inside enzyme active site could be confirmed during 50 ns. These results may be implicated in further structure-guided approaches against drug-resistant Mtb.