Integrative Computational Approaches, Molecular Docking, and Dynamic Simulations Reveal the Antimycobacterial Efficacy of Fisetin as a Potential Inhibitor of Mycobacterium tuberculosis

The development of effective antitubercular drugs is necessary because tuberculosis remains a major global healthcare burden. To examine the antimycobacterial properties of fisetin, the current study used an integrated method. The in vitro test against Mycobacterium tuberculosis H37Ra demonstrated notable inhibitory effects, with an MIC of 100µg/mL and an MBC of 200µg/mL. In silico ADMET analysis was used to assess the drug-like characteristics and advantageous pharmacokinetic parameters to explore its molecular mechanism. Significant binding affinities were observed in docking studies against eight core proteins of Mtb, with protein kinase B (PknB), a crucial Mtb regulator of cell division and survival, showing the highest affinity. Fisetin's electron stability and reactivity were revealed by DFT research, indicating that it would be able to bind to biological targets. Specifically, the stability of the fisetin-PknB complex was verified by 100-ns-scale molecular dynamics analysis, which maintained its structure and dynamics. Fisetin was shown to have similar or even better binding qualities than the anti-tubercular medication isoniazid when those were compared using docking and MD analysis. Overall, fisetin is a potential multitarget antitubercular drug that merits additional experimental validation using an integrative approach.