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

Abstract

Tuberculosis remains a major global health burden, highlighting the urgent need for novel therapeutic scaffolds with imbproved 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.