An integrated computational bioprospection of flavonoids as modulators of Mycobacterium tuberculosis decaprenylphosphoryl-β-d-ribose-2′-epimerase 1

Tuberculosis (TB) remains a significant global health threat, claiming millions of lives annually despite being preventable. The emergence of drug-resistant strains, including extensively drug-resistant TB (XDR-TB) and multidrug-resistant TB (MDR-TB), severely limits conventional treatment options. Furthermore, commonly used TB medications like isoniazid (INH) and rifampicin (RIF) are associated with adverse side effects. Consequently, researchers increasingly explore natural products as potential sources for novel anti-TB therapeutics. This study investigated the inhibitory potential of 103 flavonoid compounds with documented antimycobacterial activity against TB. Focusing on decaprenylphosphoryl-β-D-ribose 2′-epimerase 1 (DprE1) as a druggable target, we employed molecular docking, pharmacokinetic evaluation, and 200-ns molecular dynamics simulations to assess stability and energy refinement. Our results showed that the top five compounds exhibited more favourable binding free energy values against DprE1 than the standard, PBTZ169. Notably, cycloartobiloxanthone demonstrated a binding free energy of −63.67 kcal/mol, surpassing PBTZ169 (-37.78 kcal/mol). Structural analysis revealed that cycloartobiloxanthone stabilised the protein and formed additional interactions without compromising its integrity. These findings suggest a potential structural mechanism for the inhibitory action of cycloartobiloxanthone against Mycobacterium tuberculosis DprE1. While this study highlights the potential of cycloartobiloxanthone as a lead compound, further validation through in vivo and in vitro studies is recommended.