Cui Zhijie, Kang Hong, Tang Kailin, Liu Qi, Cao Zhiwei, Zhu Ruixin
Department of Bioinformatics, Tongji University, Shanghai 200092, China.
Department of Bioinformatics, Tongji University, Shanghai 200092, China ; Shanghai Center for Bioinformation Technology, Shanghai, China.
Biomed Res Int. 2015;2015:657159. doi: 10.1155/2015/657159. Epub 2015 Aug 3.
The issue of herb-drug interactions has been widely reported. Herbal ingredients can activate nuclear receptors and further induce the gene expression alteration of drug-metabolizing enzyme and/or transporter. Therefore, the herb-drug interaction will happen when the herbs and drugs are coadministered. This kind of interaction is called inductive herb-drug interactions. Pregnane X Receptor (PXR) and drug-metabolizing target genes are involved in most of inductive herb-drug interactions. To predict this kind of herb-drug interaction, the protocol could be simplified to only screen agonists of PXR from herbs because the relations of drugs with their metabolizing enzymes are well studied. Here, a combinational in silico strategy of pharmacophore modelling and docking-based rank aggregation (DRA) was employed to identify PXR's agonists. Firstly, 305 ingredients were screened out from 820 ingredients as candidate agonists of PXR with our pharmacophore model. Secondly, DRA was used to rerank the result of pharmacophore filtering. To validate our prediction, a curated herb-drug interaction database was built, which recorded 380 herb-drug interactions. Finally, among the top 10 herb ingredients from the ranking list, 6 ingredients were reported to involve in herb-drug interactions. The accuracy of our method is higher than other traditional methods. The strategy could be extended to studies on other inductive herb-drug interactions.
草药-药物相互作用的问题已被广泛报道。草药成分可激活核受体，并进一步诱导药物代谢酶和/或转运蛋白的基因表达改变。因此，当草药和药物同时给药时，就会发生草药-药物相互作用。这种相互作用被称为诱导性草药-药物相互作用。孕烷X受体（PXR）和药物代谢靶基因参与了大多数诱导性草药-药物相互作用。为了预测这种草药-药物相互作用，由于药物与其代谢酶的关系已得到充分研究，该方案可简化为仅从草药中筛选PXR的激动剂。在此，采用了一种基于药效团建模和对接排名聚合（DRA）的组合计算机模拟策略来鉴定PXR的激动剂。首先，利用我们的药效团模型从820种成分中筛选出305种成分作为PXR的候选激动剂。其次，使用DRA对药效团筛选结果进行重新排名。为了验证我们的预测，建立了一个精心策划的草药-药物相互作用数据库，该数据库记录了380种草药-药物相互作用。最后，在排名列表的前10种草药成分中，有6种成分被报道参与了草药-药物相互作用。我们方法的准确性高于其他传统方法。该策略可扩展到其他诱导性草药-药物相互作用的研究。
