Lewis David F V, Dickins Maurice, Lake Brian G, Goldfarb Peter S
School of Biomedical and Molecular Sciences, University of Surrey, Guildford, Surrey, UK.
Drug Metabol Drug Interact. 2003;19(4):257-85. doi: 10.1515/dmdi.2003.19.4.257.
Homology modelling of human CYP2C subfamily enzymes, CYP2C8, CYP2C9 and CYP2C19, based on the rabbit CYP2C5 crystal structure template is reported. The relatively high sequence homologies (75-80%) between the rabbit CYP2C5 and human CYP2C subfamily enzymes tend to indicate that the resulting structures should prove adequate models of these major catalysts of human drug metabolism. Selective substrates of all three human CYP2C enzymes are found to fit closely within the putative active sites in a manner which is consistent with site-directed mutagenesis experiments and known positions of substrate metabolism. The specific interactions between substrates and enzymes can be used to rationalize the variation in substrate binding affinity and generate QSAR models for both inhibition and metabolism via CYP2C family enzymes, yielding a generally good agreement with experimental binding data obtained from Km values, with correlation coefficients (R values) of between 0.97 and 0.99 depending on the QSAR equation produced.
报道了基于兔CYP2C5晶体结构模板对人CYP2C亚家族酶CYP2C8、CYP2C9和CYP2C19进行的同源建模。兔CYP2C5与人CYP2C亚家族酶之间相对较高的序列同源性（75 - 80%）表明，所得结构应能证明是这些人类药物代谢主要催化剂的合适模型。发现所有三种人CYP2C酶的选择性底物以与定点诱变实验和底物代谢已知位置一致的方式紧密契合在假定的活性位点内。底物与酶之间的特定相互作用可用于合理化底物结合亲和力的变化，并生成通过CYP2C家族酶进行抑制和代谢的QSAR模型，与从Km值获得的实验结合数据总体上具有良好的一致性，相关系数（R值）在0.97至0.99之间，具体取决于所产生的QSAR方程。
