Methyl 2-(7-hydroxy-3-methyloctyl)-1,3-dimethyl-4-oxocyclohex-2-enecarboxylate as a natural and potent antitubercular lead: An in silico study integrating molecular docking, molecular dynamics, FMO, and DFT analyses

The currently marketed antitubercular drugs have limited efficacy with the potential to cause organ toxicity. Thus, there is a need for new drug therapies to combat tuberculosis. Methyl 2-(7-hydroxy-3-methyloctyl)-1,3-dimethyl-4-oxocyclohex-2-enecarboxylate (PE14) and (E)-3,7,11,15-tetramethylhexadec-2-en-1-ol (EA8) are the natural antitubercular lead-like molecules isolated from petroleum ether and ethyl acetate leaf extracts of Ipomea sepiaria, respectively. Extensive research has demonstrated the wide range of health benefits associated with this plant. However, the antitubercular effects of phytocompounds isolated from this species have not been systematically investigated. To evaluate the antitubercular effect of the natural compound, in silico prediction of binding affinity against selected antitubercular target proteins was conducted, and this was compared with co-crystallized ligands as a standard. Additionally, the physicochemical properties, pharmacokinetics, and various toxicity-related parameters were also predicted. Two ligand docking complexes were selected for molecular dynamics simulations to calculate the binding free energy over 250 ns. Moreover, FMO and DFT were also investigated. PE14 complies with RO5 and exhibits suitable ADMET profiles. The molecular docking scores in kcal/mol showed comparatively more potency against antitubercular drug targets compared to the co-crystalized ligand of the target protein as well as EA8. Overall, the strength of interaction between the ligands with their selected target proteins from the molecular docking study, heat change that occurs during the ligand-target interactions from a molecular dynamic simulation study, the electronic reactivity trend was established as STD > PE14 > CIP > EA8 from FMO analysis and other multi-parametric druggability profiles of target proteins suggests that PE14 can be considered as a suitable antitubercular lead-like for the treatment of M. tuberculosis. The results of the current study were closely correlated with those of our previous study on Ipomea sepiaria in the LRP assay. However, necessary in vitro and in vivo studies on the synthesized pure compound must be carried out to participate in a clinical trial, where the in silico results would help expedite the process of drug development.