Interactions of coumarin and amine ligands with six cytochrome P450 2D6 allelic variants: Molecular docking

IF 3.1 Q2 TOXICOLOGY
Amelia Nathania Dong , Nafees Ahemad , Yan Pan , Uma Devi Palanisamy , Chin Eng Ong
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引用次数: 0

Abstract

Human CYP2D6 contributes extensively to the biotransformation of important therapeutic drugs. CYP2D6 substrate and inhibitor specificity may be affected by genetic polymorphism. This study aimed to characterize interactions of three typical ligands, 3-cyano-7-ethoxycoumarin, fluoxetine and terbinafine with six CYP2D6 variants using molecular docking simulations. The compounds were docked individually to the CYP2D6 models based on published crystal structure (PDB code: 3TBG). All ligands bound within the active site pocket near the heme. Binding involved residues found in critical secondary structures that formed the active site boundary: B-C loop, F helix, F-G loop, β-1 strands and I helix. Twenty-five amino acids were involved in the binding, and all were located in the known substrate recognition sites. Hydrophobic bonds involving phenylalanine (Phe120, Phe384) dominated CEC binding whereas electrostatic bonds between the protonated nitrogen with acidic residues (Glu216, Glu222, Asp301) dominated in binding of fluoxetine and terbinafine. Collectively, the subtle structural changes in the active site and substrate access channels induced by the mutations in the variants contributed to differential ligand docking poses. This study has provided insights into important molecular properties for CYP2D6 catalysis and inhibition, and formed basis for further exploration of structural determinants for potency and specificity of CYP2D6 ligands.

香豆素和胺配体与6种细胞色素P450 2D6等位基因变异的相互作用:分子对接
人类CYP2D6在重要治疗药物的生物转化中起着广泛的作用。CYP2D6底物和抑制剂的特异性可能受到基因多态性的影响。本研究旨在通过分子对接模拟表征3-氰-7-乙氧基香豆素、氟西汀和特比萘芬三种典型配体与6种CYP2D6变体的相互作用。根据已发表的晶体结构(PDB代码:3TBG),这些化合物分别与CYP2D6模型对接。所有的配体都结合在靠近血红素的活性位点口袋内。结合涉及在形成活性位点边界的关键二级结构中发现的残基:B-C环、F螺旋、F- g环、β-1链和I螺旋。25个氨基酸参与了这种结合,它们都位于已知的底物识别位点上。涉及苯丙氨酸的疏水性键(Phe120, Phe384)主导了CEC结合,而质子化氮与酸性残基(Glu216, Glu222, Asp301)之间的静电键主导了氟西汀和特比萘芬的结合。总的来说,变异突变引起的活性位点和底物通路的细微结构变化导致了配体对接姿势的差异。本研究揭示了CYP2D6催化和抑制的重要分子特性,为进一步探索CYP2D6配体效力和特异性的结构决定因素奠定了基础。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Computational Toxicology
Computational Toxicology Computer Science-Computer Science Applications
CiteScore
5.50
自引率
0.00%
发文量
53
审稿时长
56 days
期刊介绍: Computational Toxicology is an international journal publishing computational approaches that assist in the toxicological evaluation of new and existing chemical substances assisting in their safety assessment. -All effects relating to human health and environmental toxicity and fate -Prediction of toxicity, metabolism, fate and physico-chemical properties -The development of models from read-across, (Q)SARs, PBPK, QIVIVE, Multi-Scale Models -Big Data in toxicology: integration, management, analysis -Implementation of models through AOPs, IATA, TTC -Regulatory acceptance of models: evaluation, verification and validation -From metals, to small organic molecules to nanoparticles -Pharmaceuticals, pesticides, foods, cosmetics, fine chemicals -Bringing together the views of industry, regulators, academia, NGOs
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