In silico evaluation of phycobilins as multi-target anti-tubercular scaffolds: Molecular docking, dynamic stability, ADMET, and mycobacterial sensitivity analysis

Tuberculosis remains a major global health burden, highlighting the urgent need for novel therapeutic scaffolds with improved efficacy and multi-target activity. In this study, an integrated in silico strategy was used to investigate the anti-tubercular potential of four naturally occurring phycobilins - phycocyanobilin, phycoerythrobilin, phycourobilin, and phycoviolobilin - against a panel of essential Mycobacterium tuberculosis protein targets involved in cell wall biosynthesis, nucleic acid metabolism, energy production, and ribosomal function. Molecular docking analyses revealed consistently strong binding affinities of phycobilins toward multiple targets, often exceeding those of isoniazid and approaching the binding performance of rifampicin, indicating pronounced multi-target interaction capability. Noncovalent interaction analysis showed stable and diverse interaction networks dominated by hydrogen bonding and hydrophobic contacts. Normal mode analysis confirmed that phycobilin binding preserves intrinsic protein dynamics while inducing ligand-mediated stabilization of the protein-ligand complexes, particularly for the phycoviolobilin-InhA system. Pharmacokinetic and toxicity predictions suggested moderate distribution properties and generally favorable safety profiles, although potential mutagenicity and skin sensitization signals were identified. Additionally, mycoCSM-based predictions indicated micromolar-range anti-mycobacterial activity with limited penetration into caseous lesions. Collectively, these results support phycobilins as promising natural scaffolds for anti-tubercular drug discovery, warranting further optimization and experimental validation.