Department of Biochemistry, Faculty of Science, Mahidol University, Bangkok, Thailand ; Genomics Institute, National Center for Genetic Engineering and Biotechnology, Pathumtani, Thailand ; Department of Microbiology, University of Washington, Seattle, Washington, United States of America.
PLoS One. 2013 Sep 2;8(9):e74053. doi: 10.1371/journal.pone.0074053. eCollection 2013.
Cytochrome P450 2C9 (CYP2C9) is crucial in excretion of commonly prescribed drugs. However, changes in metabolic activity caused by CYP2C9 polymorphisms inevitably result in adverse drug effects. CYP2C9*2 and 3 are prevalent in Caucasian populations whereas CYP2C913 is remarkable in Asian populations. Single amino acid substitutions caused by these mutations are located outside catalytic cavity but affect kinetic activities of mutants compared to wild-type enzyme. To relate distal effects of these mutations and defective drug metabolisms, simulations of CYP2C9 binding to anti-coagulant (S)-warfarin were performed as a system model. Representative (S)-warfarin-bound forms of wild-type and mutants were sorted and assessed through knowledge-based scoring function. Interatomic interactions towards (S)-warfarin were predicted to be less favorable in mutant structures in correlation with larger distance between hydroxylation site of (S)-warfarin and reactive oxyferryl heme than wild-type structure. Using computational approach could delineate complication of CYP polymorphism in management of drug therapy.
细胞色素 P450 2C9（CYP2C9）在排泄常用药物方面至关重要。然而，CYP2C9 多态性引起的代谢活性变化不可避免地导致药物不良反应。CYP2C9*2 和 3 在白种人群中很常见，而 CYP2C913 在亚洲人群中很显著。这些突变引起的单个氨基酸取代位于催化腔之外，但与野生型酶相比，突变体的动力学活性受到影响。为了将这些突变的远端效应与有缺陷的药物代谢联系起来，我们以抗凝剂（S）-华法林作为系统模型，对 CYP2C9 的结合进行了模拟。通过基于知识的评分函数，对野生型和突变型的代表性（S）-华法林结合形式进行了分类和评估。与野生型结构相比，突变型结构中（S）-华法林的羟化位点与反应性氧铁血红素之间的距离更大，因此预测（S）-华法林的原子间相互作用不太有利。使用计算方法可以阐明 CYP 多态性在药物治疗管理中的复杂性。
