Natural Metabolite Ursolic Acid as an Inhibitor of Dormancy Regulator DosR of Mycobacterium tuberculosis: Evidence from Molecular Docking, Molecular Dynamics Simulation and Free Energy Analysis

Background DosR is a transcriptional regulator of Mycobacterium tuberculosis (MTB), governing the expression of a set of nearly 50 genes that is often referred to as 'dormancy regulon'. The inhibition of DosR expression by an appropriate inhibitor may be a crucial step against MTB. Objective We targeted the DosR with natural metabolites, ursolic acid (UA) and carvacrol (CV), using in silico approaches. Methods The molecular docking, molecular dynamics (MD) simulation for 200 ns, calculation of binding energies by MM-GBSA method, and ADMET calculation were performed to evaluate the inhibitory potential of natural metabolites ursolic acid (UA) and carvacrol (CV) against DosR of MTB. Results Our study demonstrated that UA displayed significant compatibility with DosR during the 200 ns timeframe of MD simulation. The thermodynamic binding energies by MM-GBSA also suggested UA conformational stability within the binding pocket. The SwissADME, pkCSM, and OSIRIS DataWarrior showed a drug-likeness profile of UA, where Lipinski profile was satisfied with one violation (MogP > 4.15) with no toxicities, no mutagenicity, no reproductive effect, and no irritant nature. Conclusion The present study suggests that UA has the potency to inhibit the DosR expression and warrants further investigation on harnessing its clinical potential.