Lewis D F, Eddershaw P J, Dickins M, Tarbit M H, Goldfarb P S
School of Biological Sciences, University of Surrey, Guildford, UK.
Chem Biol Interact. 1998 Oct 2;115(3):175-99. doi: 10.1016/s0009-2797(98)00068-4.
The structural characteristics of cytochrome P450 substrates are summarised, showing that molecular descriptors can discriminate between chemicals of differing P450 isozyme specificity. Procedures for the estimation of P450 substrate binding interaction energies and rates of metabolism are described, providing specific examples in both individual compounds binding to P450s, including those of known crystal structure, and within series of structurally related chemicals. It is demonstrated that binding energy components are primarily hydrophobic/desolvation and electrostatic/hydrogen-bonded in nature, whereas electronic factors are of importance in determining variations in reaction rates. It is thus shown that the prediction of P450 substrate binding affinities and catalytic rates may be feasible, provided that sufficient structural information is available for the relevant enzyme-substrate complex.
总结了细胞色素P450底物的结构特征，表明分子描述符可区分具有不同P450同工酶特异性的化学物质。描述了估算P450底物结合相互作用能和代谢速率的方法，并在与P450结合的单个化合物（包括已知晶体结构的化合物）以及一系列结构相关的化学物质中给出了具体示例。结果表明，结合能成分主要是疏水性/去溶剂化和静电/氢键性质，而电子因素在决定反应速率的变化中很重要。因此表明，只要有足够的相关酶-底物复合物的结构信息，预测P450底物结合亲和力和催化速率可能是可行的。
