ABSTRACT The emergence of multidrug‐resistant tuberculosis (MDR‐TB) and the zoonotic transmission of Mycobacterium bovis to humans highlight the urgent need for multitarget and cross‐species therapeutic strategies. This study presents a multitarget, cross‐species in silico approach that extends beyond traditional single‐target TB drug discovery by identifying natural product scaffolds predicted to inhibit InhA and DprE1 in Mycobacterium tuberculosis and repurposing them as potential BioA inhibitors in both M. tuberculosis and M. bovis . An integrated computational workflow combining E‐pharmacophore modeling, virtual screening of the COCONUT natural product database, absorption, distribution, metabolism, excretion, and toxicity (ADMET) profiling, Molecular Mechanics Generalized Born Surface Area (MM‐GBSA) analysis, molecular dynamics (MD) simulations, and density functional theory (DFT) calculations was employed. Pharmacophore‐guided screening of ∼695,000 natural products prioritized five compounds with favorable pharmacokinetic properties and binding energies. Among these, MT5 and MT2 showed comparatively favorable predicted binding profiles relative to co‐crystal ligands and reference drugs (isoniazid and macozinone), maintained stable interactions during MD simulations, and exhibited favorable DFT descriptors. MT5 demonstrated predicted multitarget inhibition of InhA and DprE1, while MT2 showed predicted cross‐species binding compatibility with BioA from both M. tuberculosis and M. bovis . Overall, this study proposes a One Health–aligned computational framework and identifies promising natural product–derived scaffolds for future experimental validation toward broad‐spectrum antimycobacterial drug development.
Nair et al. (Sun,) studied this question.