PhototoxicityMedicinal Chemistry Strategies for Risk Mitigation in Drug Discovery

Phototoxicity is a common safety concern encounteredby projectteams in pharmaceutical research and has the potential to stop progressionof an otherwise promising candidate molecule. This perspective aimsto provide an overview of the approaches toward mitigation of phototoxicitythat medicinal chemists have taken during the lead optimization phasein the context of regulatory standards for photosafety evaluation.Various strategies are laid out based on available literature examplesin order to highlight how structural modification can be utilizedtoward successful mitigation of a phototoxicity liability. A proposedflowchart is presented as a guidance tool to be used by the practicingmedicinal chemist when facing a phototoxicity risk. The descriptionof available tools to consider in the drug design process will includean overview of the evolution of in silico methods and their applicationas well as structure alerts for consideration as potential phototoxicophores.