参与外源性物质代谢的人类细胞色素P450的同源性建模及底物选择性的合理化分析

Homology modelling of human cytochromes P450 involved in xenobiotic metabolism and rationalization of substrate selectivity.

作者信息

Lewis D F

机构信息

School of Biological Sciences, University of Surrey, UK.

出版信息

Exp Toxicol Pathol. 1999 Jul;51(4-5):369-74. doi: 10.1016/S0940-2993(99)80024-4.

DOI:10.1016/S0940-2993(99)80024-4

PMID:10445400

Abstract

Molecular modelling of human cytochrome P450 (CYP) isoforms is described, based on amino acid sequence homology with a unique bacterial P450 (CYP102) of known crystal structure. It is found that for the human hepatic P450s involved in the metabolism of xenobiotics, ie. CYPIA2, CYP 1A6, CYP2B6, CYP2C9, CYP2C 19, CYP2D6, CYP2E1 and CYP3A4, there is a satisfactory agreement between specific substrate characteristics and topographical features of the putative active sites, including complementarity with key amino acid residues in the P450 haem environments. A combination of homology model interactions with substrates and certain molecular properties of the compounds themselves provides a methodology for the evaluation of potential P450 selectivity in new chemical entities (NCEs).

摘要

基于与已知晶体结构的独特细菌细胞色素P450（CYP）（CYP102）的氨基酸序列同源性，对人类细胞色素P450（CYP）亚型进行了分子建模。研究发现，对于参与外源性物质代谢的人类肝脏细胞色素P450，即CYPIA2、CYP 1A6、CYP2B6、CYP2C9、CYP2C 19、CYP2D6、CYP2E1和CYP3A4，特定底物特征与假定活性位点的拓扑特征之间存在令人满意的一致性，包括与细胞色素P450血红素环境中关键氨基酸残基的互补性。同源模型与底物的相互作用以及化合物本身的某些分子特性相结合，为评估新化学实体（NCEs）中潜在的细胞色素P450选择性提供了一种方法。