Photochemical Degradation and In-Silico Studies of Venlafaxine: A Photosensitizing Antidepressant Drug.

The photochemical behavior of the phototoxic antidepressant drug venlafaxine (VLF, 1) was studied under aerobic conditions in UV-A light. Irradiation of a phosphate buffer solution of the drug produces N-Demethylated (2) and O-Demethylated (3) as two major photoproducts. The formation of photoproducts (2) and (3) occurs through a singlet oxygen-mediated mechanism, i.e., type-II photodynamic action, involving an irreversible trapping of the self-photogenerated singlet molecular oxygen (1O2) and through free radical-mediated mechanism, i.e., type 1 photodynamic action, respectively. The generation of singlet oxygen and free radicals during photolysis was confirmed by singlet oxygen scavenger sodium azide (NaN3) and free radical scavenger reduced glutathione (GSH). In addition, the comparative antioxidant potentials of the parent drug and its photoproducts were examined utilizing in-silico molecular docking against tyrosinase to better understand the in vivo relevance of drug pharmacological action as a result of drug-light interaction. Photoproduct (2) exhibited less activity as compared to the parent drug, VLF (1), whereas photoproduct (3) formed a stable protein–ligand complex. In order to determine the nature of stability of complex between protein and ligand, further, molecular dynamics (MD) simulation on photoproduct (3) was performed for 100 ns, and the results were analyzed by monitoring root mean square deviations (RMSD), the radius of gyration (Rg), and solvent accessible surface area (SASA). The results proved the formation of a better protein–ligand complex with photoproduct (3). These findings imply that drug users should avoid their exposure to light (natural or artificial) to prevent drug-induced photosensitivity. This study also opens new vistas for the development of novel drugs with desired tyrosinase binding affinity, improved biological features, and low phototoxic manifestations. [ABSTRACT FROM AUTHOR]