Out-compute drug side effects: Focus on cytochrome P450 2D6 modeling

Understanding the way in which drugs are metabolized by cytochrome P450 2D6 (CYP2D6) and hence the underlying mechanisms that define potential toxicity is crucial to avoid adverse reactions. The high occurrence of CYP2D6 polymorphs enhances the complexity of the toxicity assessment of a drug candidate and should be tackled from early drug discovery phase on. The recent increase in available mammalian CYP2D6 X‐ray structures opens the gateway to the development of in silico three‐dimensional CYP2D6 toxicity prediction techniques that address also the major clinically relevant allelic variants. This review presents the basic principles needed for comprehending the enzyme particularities, gives a concise overview of several clinical relevant allelic CYP2D6 variants, and explores the state‐of‐the‐art CYP2D6 research field to accelerate the development and use of such integrative in silico modeling technologies. This article is categorized under: • Structure and Mechanism > Computational Biochemistry and Biophysics • Structure and Mechanism > Molecular Structures • Software > Molecular Modeling