Molecular modelling of the human cytochrome P450 isoform CYP2A6 and investigations of CYP2A substrate selectivity

被引:45
作者
Lewis, DFV [1 ]
Dickens, M
Lake, BG
Eddershaw, PJ
Tarbit, MH
Goldfarb, PS
机构
[1] Univ Surrey, Sch Biol Sci, Guildford GU2 5XH, Surrey, England
[2] Glaxo Wellcome Res & Dev Ltd, Ware SG12 0DP, Herts, England
[3] BIBRA Int, Carshalton SM5 4DS, Surrey, England
关键词
coumarin; 7-hydroxylase; CYP2A6; molecular modelling; substrate selectivity;
D O I
10.1016/S0300-483X(98)00149-8
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
(1) The generation of a homology model of CYP2A6, the major catalyst of human hepatic coumarin 7-hydroxylase activity, involves the use of the recently published substrate-bound CYP102 crystal structure as a template. (2) A substantial number of structurally diverse CYP2A6 substrates are found to dock satisfactorily within the putative active site of the enzyme, leading to the formulation of a structural template (or pharmacophore) for CYP2A6 specificity/selectivity. (3) The CYP2A6 model is consistent with available evidence from site-directed mutagenesis studies carried out on CYP2A subfamily isoforms, and enables some explanation of species differences in CYP2A-mediated metabolism of certain substrates. (4) Quantitative structure-activity relationship (QSAR) analysis of CYP2A5 (the mouse orthologue) mutants yields statistically significant correlations between various properties of amino acid residues and coumarin 7-hydroxylase activity. (C) 1999 Elsevier Science Ireland Ltd. All rights reserved.
引用
收藏
页码:1 / 33
页数:33
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