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

Abstract

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

Spontaneous Ligand Access Events to Membrane-Bound Cytochrome P450 2D6 Sampled at Atomic Resolution

“…The correlation was especially evident at the example of simulation #3, where a slight displacement of the ligand from its favored pose in the active site directly caused a substantial weakening of the hydrophobic energy. Even though not all simulations showed a clear correlation (#4 and #5), most of them presented a trend for a gain in hydrophobic energy during the translocation from the enzyme surface to the buried active site, where the known hydrophobic environment 1,15 seemed to offer a favorable milieu for the ligands. The relatively fast access of both non-polar BTD molecules added additional evidence for the relevance of hydrophobicity.…”

“…In addition, the enzyme is subject to a high interindividual variation in metabolic performance due to a genetic polymorphism. In drug therapy, this can ultimately lead to either severe adverse effects or the suppression of a therapeutic effect 1 . The allelic variant CYP2D6*53, which harbors the two amino acid mutations F120I and A122S, shows an increased metabolic rate towards several substrates in experiments indicating a pending designation as ultrarapid metabolizer (UM) phenotype 2–7 .…”

“…The active site of CYPs is located in a buried cavity inside the enzyme that is connected to the surrounding environment by tunnels 2,8–14 . These tunnels are believed to influence both the poorly understood substrate specificity and binding kinetics of CYPs 1,11,13,15 . As the prediction of CYP metabolism is of major importance for drug development 1 , the influence of enzyme tunnels on small molecule binding has been intensively investigated 2,10,13,16,17 .…”

“…These tunnels are believed to influence both the poorly understood substrate specificity and binding kinetics of CYPs 1,11,13,15 . As the prediction of CYP metabolism is of major importance for drug development 1 , the influence of enzyme tunnels on small molecule binding has been intensively investigated 2,10,13,16,17 . Available experimental methods have only limited applicability for the determination and characterization of enzyme tunnels or complex transport phenomena.…”

In Silico Pharmacogenetics CYP2D6 Study Focused on the Pharmacovigilance of Herbal Antidepressants

“…The prediction of interactions of the natural compounds with one major class of drug metabolizing enzymes, cytochromes P450, especially the family member CYP2D6, is of particular interest. This isoform is responsible for biotransformation of about 25% of all the marketed drugs, and displays a very high polymorphism rate (Zhou, 2009;Don and Smiesǩo, 2018). Inhibition or induction of CYP2D6 metabolism can alter the pharmacokinetic profile of the concomitantly administered drug and potentially can lead to toxicity or affect the drug efficacy (Singh and Zhao, 2017).…”