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

## TL;DR

This study identifies deep-sea marine compounds that could inhibit a key enzyme in tuberculosis bacteria, offering new drug development potential.

## Contribution

A novel computational pipeline identifies deep-sea metabolites as potential inhibitors of the F420-dependent oxidoreductase in Mycobacterium tuberculosis.

## Key findings

- Three marine metabolites showed strong binding affinity to the Rv1155 enzyme.
- Upenamide exhibited the strongest and most stable interaction during simulations.
- The screening pipeline offers a cost-effective framework for future drug discovery.

## Abstract

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 2773 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 identified 68 metabolites with strong affinity (−10.98 to −15.95 kcal/mol) for the Rv1155 binding pocket, and from which three compounds, Upenamide (CMNPD_22964), Aspyronol (Compound_1749), and Fiscpropionate F (Compound_1796), were shortlisted as hit candidates. Among these, Upenamide displayed the strongest binding (ΔG = −28.56 kcal/mol) with stable RMSD and hydrogen bond persistence during 100 ns MD simulation, while Aspyronol demonstrated a promising ADMET profile comparable to the native cofactor F4202. MM-GBSA analysis further confirmed the strong binding strength (ΔG _bind = −24.77 to −34.07 kcal/mol) for all three hit candidates. These findings confirm the strong and stable interaction of selected deep-sea marine metabolites with Rv1155. This validated screening pipeline established here provides a cost-effective framework for future experimental validation and expansion to additional F420-related drug targets in M. tb.