Barr John T, Jones Jeffrey P, Oberlies Nicholas H, Paine Mary F
Experimental and Systems Pharmacology, College of Pharmacy, Washington State University, Spokane, Washington (J.T.B., M.F.P.); Department of Chemistry, Washington State University, Pullman, Washington (J.P.J.); and Department of Chemistry and Biochemistry, University of North Carolina at Greensboro, Greensboro, North Carolina (N.H.O.).
Experimental and Systems Pharmacology, College of Pharmacy, Washington State University, Spokane, Washington (J.T.B., M.F.P.); Department of Chemistry, Washington State University, Pullman, Washington (J.P.J.); and Department of Chemistry and Biochemistry, University of North Carolina at Greensboro, Greensboro, North Carolina (N.H.O.)
Drug Metab Dispos. 2015 Jan;43(1):34-41. doi: 10.1124/dmd.114.061192. Epub 2014 Oct 17.
The mechanistic understanding of interactions between diet-derived substances and conventional medications in humans is nascent. Most investigations have examined cytochrome P450-mediated interactions. Interactions mediated by other phase I enzymes are understudied. Aldehyde oxidase (AO) is a phase I hydroxylase that is gaining recognition in drug design and development programs. Taken together, a panel of structurally diverse phytoconstituents (n = 24) was screened for inhibitors of the AO-mediated oxidation of the probe substrate O(6)-benzylguanine. Based on the estimated IC50 (<100 μM), 17 constituents were advanced for Ki determination. Three constituents were described best by a competitive inhibition model, whereas 14 constituents were described best by a mixed-mode model. The latter model consists of two Ki terms, Kis and Kii, which ranged from 0.26-73 and 0.80-120 μM, respectively. Molecular modeling was used to glean mechanistic insight into AO inhibition. Docking studies indicated that the tested constituents bound within the AO active site and elucidated key enzyme-inhibitor interactions. Quantitative structure-activity relationship modeling identified three structural descriptors that correlated with inhibition potency (r(2) = 0.85), providing a framework for developing in silico models to predict the AO inhibitory activity of a xenobiotic based solely on chemical structure. Finally, a simple static model was used to assess potential clinically relevant AO-mediated dietary substance-drug interactions. Epicatechin gallate and epigallocatechin gallate, prominent constituents in green tea, were predicted to have moderate to high risk. Further characterization of this uncharted type of interaction is warranted, including dynamic modeling and, potentially, clinical evaluation.
对人类饮食衍生物质与传统药物之间相互作用的机制理解尚处于起步阶段。大多数研究都考察了细胞色素P450介导的相互作用。由其他I相酶介导的相互作用研究较少。醛氧化酶（AO）是一种I相羟化酶，在药物设计和开发项目中越来越受到关注。综合起来，对一组结构多样的植物成分（n = 24）进行了筛选，以寻找AO介导的探针底物O(6)-苄基鸟嘌呤氧化的抑制剂。根据估计的IC50（<100 μM），推进了17种成分的Ki测定。三种成分最适合用竞争性抑制模型描述，而14种成分最适合用混合模式模型描述。后一种模型由两个Ki项组成，Kis和Kii，分别范围为0.26 - 73和0.80 - 120 μM。分子建模用于深入了解AO抑制的机制。对接研究表明，测试的成分结合在AO活性位点内，并阐明了关键的酶-抑制剂相互作用。定量构效关系建模确定了三个与抑制效力相关的结构描述符（r(2) = 0.85），为开发仅基于化学结构预测外源性物质AO抑制活性的计算机模型提供了框架。最后，使用一个简单的静态模型来评估潜在的临床相关AO介导的饮食物质-药物相互作用。表没食子儿茶素没食子酸酯和表儿茶素没食子酸酯是绿茶中的主要成分，预计具有中度到高度风险。有必要对这种未知类型的相互作用进行进一步表征，包括动态建模以及可能的临床评估。
