Deep-Sea Marine Metabolites as Promising Anti-Tubercular Agents: CADD-Guided Targeting of the F420-Dependent Oxidoreductase

Tuberculosis, caused by Mycobacterium tuberculosis (M. tb), remains a leading global threat, escalated now by the rise of multidrug-resistant (MDR-TB) and extensively drug-resistant (XDR-TB) strains. In search of a novel anti-tubercular agent with a distinct mechanism of action, this study explores deep-sea marine metabolites as potential inhibitors of the F₄₂₀-dependent oxidoreductase Rv1155, a redox enzyme essential for M. tb survival. A total of 2,773 marine-derived compounds curated from the CMNPD, Reaxys, and MarinLit databases were screened using an integrated CADD workflow combining molecular docking, in-silico ADMET profiling, and molecular dynamics (MD) simulations. Docking results revealed several metabolites with high affinity for the Rv1155 binding pocket, and three compounds: Upenamide (CMNPD_22964), Aspyronol (Compound_1749), and Fiscpropionate F (Compound_1796) as hit candidates. Among these, Upenamide displayed the strongest binding and stable protein-ligand dynamics, while Aspyronol demonstrated a promising ADMET profile comparable to that of the native cofactor F₄₂₀₂. These findings highlight the potential of deep-sea marine metabolites as a valuable source of anti-tubercular scaffolds and establish a computationally driven, cost-effective framework for discovering inhibitors targeting F₄₂₀-dependent enzymes. This approach provides a foundation for future experimental validation and expansion to additional F₄₂₀-related drug targets in M. tb.