Structure-Based Virtual Screening of Seaweed Metabolite Database Against Shikimate Kinase of Mycobacterium tuberculosis: Identification of Dichotenone-A as a Promising Anti-Tuberculosis Lead Compound

Tuberculosis (TB), caused by Mycobacterium tuberculosis, remains the world's leading infectious disease killer, claiming 1.25 million lives in 2023 alone. The global TB crisis is further compounded by the emergence of multidrug-resistant (MDR-TB) and extensively drug-resistant (XDR-TB) strains, which render conventional drug regimens ineffective, prolonged, and highly toxic. The shikimate pathway, absent in mammals but indispensable in M. tuberculosis, presents a uniquely selective therapeutic target. Shikimate kinase (SK), the fifth enzyme of this pathway, catalyses the ATP-dependent phosphorylation of shikimate to shikimate-3-phosphate and is encoded by the essential aroK gene. In this study, a structure-based virtual screening approach was employed to screen 1,191 compounds from the Seaweed Metabolite Database (SWMD) against the crystal structure of MtSK (PDB: 8X5S). Compounds were filtered through drug-likeness rules (Lipinski, Veber, Egan, Ghose, GSK 4/400, Pfizer), ADME profiling (SwissADME), and toxicity assessment (ProTox-3). After rigorous filtration, 69 compounds were selected for molecular docking using AutoDock Vina. The marine diterpene Dichotenone-A (BD002) from Dictyota bartayresiana demonstrated the best binding energy of −8.9 kcal/mol, interacting with active-site residues of MtSK identical to those occupied by the co-crystallized ligand. RMSF analysis using CABSflex 3.0 validated structural stability of the protein-ligand complex. These findings establish Dichotenone-A as a promising zero-toxicity natural lead compound for anti-TB drug development, warranting further in vitro and in vivo validation.