利用重定位策略从中药中发现L-型钙离子通道作用降压药

Discovering L-type calcium channels inhibitors of antihypertensive drugs based on drug repositioning

该文以来源于NCBI数据库中对新西兰兔心脏L-型钙离子通道具有抑制作用的12个化合物为研究对象,利用Hip Hop定性药效团模型构建方法,建立L-型钙离子通道拮抗剂的药效团模型,利用数据库搜索方法对药效团模型进行优劣评价,同时,以所得的最优药效团模型对Drugbank和TCMD进行筛选,通过匹配程度和文献验证分别对从Drugbank中筛选所得的已上市药物进行降压作用重定位和从TCMD中筛选所得中药有效成分进行降压作用评价。结果获得最优药效团模型具有2个氢键受体和4个疏水基团,其综合评价指数CAI为2.78,从Drugbank中筛选的已上市药物93个,从TCMD筛选的中药有效成分285个。该文所构建的定性药效团具有一定的可靠性,可用于活性化合物筛选;Drugbank中筛得化合物,如普伐他汀,具有潜在的L-型钙离子通道抑制作用;TCMD筛选的中药化学成分,如白花前胡素Ⅲ、牛蒡苷元是潜在的降压药物。该策略有助于从中药中开展L-型钙离子通道的药物重定位研究。

This study was amid to construct the pharmacophore model of L-type calcium channel antagonist in the application of screening Drugbank and TCMD. This paper repositions the approved drugs resulting from virtual screening and discusses the relocationbased drug discovery methods,screening antihypertensive drugs with L-type calcium channel function from TCMD. Qualitative hypotheses wre generated by Hip Hop separately on the basis of 12 compounds with antagonistic action on L-type calcium channel expressed in rabbit cardiac muscle. Datebase searching method was used to evaluate the generated hypotheses. The optimum hypothesis was used to search Drugbank and TCMD. This paper repositions the approved drugs and evaluates the antihypertensive effect of the chemical constituent of traditional Chinese medicine resulting from virtual screening by the matching score and literature. The results showed that optimum qualitative hypothesis is with six features,which were two hydrogen-bond acceptors,four hydrophobic groups,and the CAI value of 2. 78. Screening Drugbank achieves 93 approved drugs. Screening TCMD achieves 285 chemical constituents of traditional Chinese medicine. It was concluded that the hypothesis is reliable and can be used to screen datebase. The approved drugs resulting from virtual screening,such as pravastatin,are potentially L-type calcium channels inhibitors. The chemical constituents of traditional Chinese medicine,such as Arctigenin Ⅲ and Arctigenin are potentially antihypertensive drugs. It indicates that Drug Repositioning based on hypothesis is possible.