Managing the Liabilities Arising from Structural Alerts: A Safe Philosophy for Medicinal Chemists
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; covalent protein modification; hepatotoxicity; macromolecules; mechanism based CYP inactivation; metabolic switching; reactive electrophilic species; reactive intermediates; xenobiotics
Document Type: Research Article
Publication date: July 1, 2011
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