Zhu Ruixin, Hu Liwei, Li Haiyun, Su Juan, Cao Zhiwei, Zhang Weidong
Department of Natural Medicinal Chemistry, School of Pharmacy, Second Military Medical University, Shanghai 200433, China; E-Mails:
Int J Mol Sci. 2011;12(5):3250-62. doi: 10.3390/ijms12053250. Epub 2011 May 18.
Inhibition of cytochrome P450 (CYP) is a major cause of herb-drug interactions. The CYP1A2 enzyme plays a major role in the metabolism of drugs in humans. Its broad substrate specificity, as well as its inhibition by a vast array of structurally diverse herbal active ingredients, has indicated the possibility of metabolic herb-drug interactions. Therefore nowadays searching inhibitors for CYP1A2 from herbal medicines are drawing much more attention by biological, chemical and pharmological scientists. In our work, a pharmacophore model as well as the docking technology is proposed to screen inhibitors from herbal ingredients data. Firstly different pharmaphore models were constructed and then validated and modified by 202 herbal ingredients. Secondly the best pharmaphore model was chosen to virtually screen the herbal data (a curated database of 989 herbal compounds). Then the hits (147 herbal compounds) were continued to be filtered by a docking process, and were tested in vitro successively. Finally, five of eighteen candidate compounds (272, 284, 300, 616 and 817) were found to have inhibition of CYP1A2 activity. The model developed in our study is efficient for in silico screening of large herbal databases in the identification of CYP1A2 inhibitors. It will play an important role to prevent the risk of herb-drug interactions at an early stage of the drug development process.
细胞色素P450（CYP）的抑制是草药与药物相互作用的主要原因。CYP1A2酶在人体药物代谢中起主要作用。其广泛的底物特异性，以及大量结构多样的草药活性成分对它的抑制作用，表明了代谢性草药与药物相互作用的可能性。因此，如今从草药中寻找CYP1A2抑制剂受到了生物、化学和药理学家的更多关注。在我们的工作中，提出了一种药效团模型以及对接技术，用于从草药成分数据中筛选抑制剂。首先构建不同的药效团模型，然后用202种草药成分进行验证和修改。其次，选择最佳的药效团模型对草药数据（一个包含989种草药化合物的精选数据库）进行虚拟筛选。然后，通过对接过程继续筛选命中的化合物（147种草药化合物），并依次进行体外测试。最后，发现18种候选化合物（272、284、300、616和817）中有5种具有抑制CYP1A2活性的作用。我们研究中开发的模型对于在计算机上筛选大型草药数据库以鉴定CYP1A2抑制剂是有效的。它将在药物开发过程的早期阶段预防草药与药物相互作用的风险方面发挥重要作用。
