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 K E Y W O R D S adverse effects, CYP2D6, cytochrome P450, polymorphism, rational drug design, toxicity 1 | INTRODUCTION 1.1 | Cytochrome P450 2D6 metabolic relevance in drug discoveryEarly toxicity evaluation is of great importance to improve the worrying drug attrition rates. In the last two decades, tighter drug safety regulations steered the pharmaceutical industry to invest more time and resources in reduction of drug failures due to toxicity in early drug development (Waring et al., 2015). Accurate prediction of the toxicity profile of a potential drug candidate is a multifaceted challenge, especially since in essence all molecules are toxic to some degree for living organisms. To define the border between toxic and nontoxic, both the pharmacokinetics and the pharmacodynamics of the drug need to be assessed. Absorption, distribution, metabolism, and excretion processes strongly impact the bioavailability and hence the extent of drug toxicity in the body. Xenobiotic metabolism is a critical process in drug clearance and avoiding any potential metabolic liability is one of the major endpoints addressed in assessment studies during the early phase clinical trials. Drugs administered orally can either be readily excreted or undergo a metabolic biotransformation by chemical modification of the compound into a more soluble product facilitating the renal excretion. The generally known four types of hepatic reactions during the biotransformation are categorized into phase I (oxidation, hydrolysis, and reduction) and phase II (conjugation). Phase I reactions are dominated by the cytochrome enzyme P450 superfamily (abbreviated P450 henceforth). Cytochrome
