具有质子泵双抑制机理中药成分筛选研究

质子泵抑制剂能有效治疗胃酸相关疾病，目前上市及处于临床研究的药物有不可逆型和可逆型两种作用机理。如果一个先导化合物能够同时符合这两种作用机理，势必有望成为更加有效的质子泵抑制剂。借助于先进的分子模拟技术，该文首先分别构建了这两种作用机理的药效团模型。测试集阳性正确率（大于70％）和阴性正确率（大于90％）表明，模型具有较强的预测能力和合理性。由于70％的现有药物仍然直接或间接的来源于中药成分，因此，本课题选择在中药成分数据库中开展质子泵双抑制机理先导化合物的虚拟筛选研究。运用空间多样性子集法，首先选取1000个代表性中药成分作为候选分子。进一步运用构建的两个药效团模型共同过滤，发现26个中药成分可作为兼具不可逆型和可逆型双机理的先导化合物。其中化合物14来源于治疗胃脘疼痛的中药材九里香，为从分子水平解释中成药“三九胃泰”的作用机理提供了思路。本课题研究方法同样适用于其它疾病的中药成分筛选研究。

Virtual Screening of Dual-Mechanism Proton Pump Inhibitors of Traditional Chinese Medicine

Proton pump inhibitors could effectively treat acid-related diseases, Drugs marketed and in clinical trials mainly include irreversible and reversible types. One leading compound with both mechanisms would potentially become more potent proton pump inhibitor. With advanced molecular simulation technique, pharmacophore models of both mechanisms were built in our study. Positive accuracy （ over 70% ） and negative accuracy （ over 90% ） indicated that models showed high prediction ability. Since 70% of current drugs marketed derived from traditional Chinese medicine, we performed virtual screening of dual-mechanism proton pump inhibitors through traditional Chinese medicine database. Diverse subset was utilized to select 1000 compounds as candidates. Pharmacophore models were further employed to obtain 26 compounds taken as dual-mechanism leading compound of both irreversible and reversible mechanisms. Among them, compound 14 derived from Murraya paniculata which is used to treat gastralgia. This study provides an understanding of mechanism of Sanjiu Weitai Capsules at the molecular level. Our method could be applied to other virtual screening studies of traditional Chinese medicine as well.