Managing the Liabilities Arising from Structural Alerts: A Safe Philosophy for Medicinal Chemists

P.      J. Edwards; C.      Sturino

doi:10.2174/092986711796391714

Abstract

Bioactivation of xenobiotics can, in certain circumstances, result in the formation of reactive electrophilic species. These reactive metabolites may covalently modify proteins and macromolecules and it has been suggested that protein modification is a key initial step in provoking idiosyncratic adverse drug reactions. Understanding these bioactivation pathways is critical in order to rationally design drug candidates with a lower propensity to form reactive intermediates. Herein, we provide an overview of the importance of Structural Alerts and bioactivation pathways and describe the creation of an in-house database as a tool aimed at informing medicinal chemists about these potential liabilities.

Keywords: Structural alerts, bioactivation, hepatotoxicity, mechanism based CYP inactivation, metabolic switching, covalent protein modification, reactive intermediates, xenobiotics, reactive electrophilic species, macromolecules