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WIREs Comput Mol Sci
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Out‐compute drug side effects: Focus on cytochrome P450 2D6 modeling

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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
Cytochrome P450 2D6 (CYP2D6) environment displaying the three major components required for the catalytic cycle. (a) Molecular environment of cytochrome P450: CYP2D6 (497 aa) anchored (drawn part) to the membrane (endoplasmic reticulum) at its N‐terminus side (pink, PDB 4WNU; www.rcsb.org) together with its redox partner NADPH‐cytochrome P450 reductase (CPR, 676 aa) (cyan, PDB 1AMO; www.rcsb.org). CPR shuttles the electrons from nicotinamide adenine dinucleotide phosphate (NADPH) to the CYP where they are used for the catalytic oxidation of tamoxifen into 4‐hydroxtamoxifen (afimoxifene). It is proposed that lipophilic substrates can access the active site directly through the membrane (pathway II) in addition to the cytosolic entry (pathway I) (Scott et al., ). (b) General catalytic cycle of a P450 substrate: In the resting state of CYP2D6, a water molecule is covalently bound to the iron (III) (A). Upon binding of a substrate to the ferric enzyme, the distal water is displaced as the sixth heme ligand (B). The first reduction of the iron (III) complex reduces the iron to the (deoxy) iron (II) state, also known as “the ferrous state” (C). This enables the binding of a molecular oxygen, forming a ferrous oxyiron (II) complex (D). The second reduction results in an activated oxygen species (E). Addition of a proton leads to the iron (II)‐peroxide intermediate (F). The second protonation permits a heterolytic oxygen–oxygen bond scission, and a water molecule leaves (one oxygen atom with two protons and electrons) resulting in the iron (IV) coupled porphyrin radical cation (G). This highly reactive oxyferryl intermediate inserts an oxygen atom into the substrate, producing the oxidized product (R‐OH) (H). Dissociation of the product turns the cytochrome back to its initial resting state (A). All structural images were generated with the PyMol Molecular Graphics System (version 2.0, Schrödinger, LLC, New York, NY)
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Overview of computational strategies applied in cytochrome P450 2D6 toxicology modeling. If experimental atomic data on the target is available, a structure‐based or combined (ligand‐ and structure‐based) approach is advantageous. This enables modeling the ligand in the native binding pocket with increased accuracy meaning a more reliable prediction of possible toxicology‐relevant binding phenomena. With no experimental (or poor quality) data on the target only the ligand‐based approach is available (Boyer et al., ; Cruciani et al., ; Li, Schneebeli, Bylund, Farid, & Friesner, ; Rydberg, Gloriam, Zaretzki, Breneman, & Olsen, ; Terfloth, Bienfait, & Gasteiger, ; Vedani, Dobler, Hu, & Smieško, )
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Metabolic pathway of cytochrome P450 2D6 (CYP2D6)‐dependent drug codeine (Crews et al., ). Codeine is metabolized (O‐demethylation) into morphine by CYP2D6 (~15%, pink, PDB 4WNU; www.rcsb.org). Morphine and the secondary metabolite (morphine‐6‐glucuronide) are essential for the analgesic effect (denoted with an asterisk). Morphine is further metabolized by UGT2B7 (~60%, gold, PDB 206L; www.rcsb.org) into morphine‐3‐glucuronide and by CYP3A4/2C8 (~10%, gold, PDB 4D6Z; www.rcsb.org) into normorphine. Two additional codeine clearance pathways are (a) UGT2B7 (~ 70%) which forms codeine‐6‐glucuronice and (b) CYP3A4 (~15%) which forms norcodeine
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Cytochrome P450 2D6 (CYP2D6) polymorphism distribution among Caucasians. (a) the genetic modification is shown (normal = black; impaired = red gene; explained in table B) with the corresponding phenotype, enzyme activity, and its relative frequency (Zhou et al., ). Depending on the genetic differences among patients, the phenotypes are categorized as ultrarapid (UM), normal (NM), intermediate (IM), or poor (PM) metabolizers (Caudle et al., ). Among Caucasians, the dominant phenotype is NM, followed by IM, PM, and UM. (b) Overview of different phenotypes and the corresponding genotypic description
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Cytochrome P450 2D6 (CYP2D6) (PDB 3QM4; www.rcsb.org) structural characteristics. (a) CYP2D6 is displayed with annotated secondary structural elements. The α‐helices are shown in white, β‐sheets in pink, and loops in cyan. The FG and BC loop, important for regulation of the binding cavity access, are highlighted in orange. The CYP2D6 core of the active site cavity is formed by amino acids located on helices I, F, G, loop KL and FG, and the heme. Based on previous studies, residues suggested to form the active site include Asp100, Pro103, Ile106, Thr107, Leu110, Pro114, Ser116, Gln117, Phe120, Leu121, Ala122, Leu213, Glu216, Phe219, Asp301, Ser304, Ala305, Thr309, Trp316, Val370, Pro371, Gly373, Val374, Val480, Phe481, and Phe483. A particular role for some of these residues has been established by experiment (Rowland et al., ; Wang et al., ). (b) Same CYP2D6 structure as shown in (a) but rotated to match the orientation shown in (c). (c) the six major substrate recognition sites (SRS) (Gotoh, ) are displayed and located around: The B′ helix (SRS1, gray), the F helix (SRS2, orange), the G‐helix (SRS3, pink), the I helix (SRS4, green), beta 4‐1 (SRS5, yellow), and beta 4‐2/3‐2 (SRS6, blue)
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Structure and Mechanism > Molecular Structures
Structure and Mechanism > Computational Biochemistry and Biophysics
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