基于药效团技术与专利检索的降脂中药发现研究  

Study on lipid-lowering traditional Chinese medicines based on pharmacophore technology and patent retrieval

作　　者：霍晓乾 贺昱甦 乔连生[1] 孙志一 张燕玲[1] 

机构地区：[1]北京中医药大学中药信息工程研究室,北京100102 [2]北京东方灵盾科技有限公司,北京100191

出　　处：《中国中药杂志》2014年第24期4839-4843,共5页China Journal of Chinese Materia Medica

基　　金：国家自然科学基金项目(81173522);基于源头创新的中药孵化基地建设项目(2011ZX09401-028);北京市与中央在京高校共建项目(BJGJ1412)

摘　　要：抑制HMG-Co A还原酶的他汀类药物与激动PPAR-α的贝特类药物联合应用相较于单纯应用能产生更好的降脂效果,但同时也会产生较强的不良反应。中药与HMG-Co A还原酶抑制剂合用治疗高血脂疗效稳定、毒副作用小,为药物联用提供了新的选择。该文利用药效团技术搜索中药化学成分,追溯其来源中药,确定潜在的具有PPAR-α激动活性的常用中药。由于现有中医经典中未涉及治疗高脂血症的相关用药方案以供参考,为确保所选中药的联合应用具有较高的安全性和有效性,该文选择世界传统药物专利数据库中已有临床验证的能与他汀类药物联合降脂之中药,并据此分析药效团命中结果中的相应药物,最终获得能作用于PPAR-α且能与他汀类药物联合使用的常用中药。其中,药效团模型以PPAR-α的8个配体-受体结合物为研究对象,利用DS程序中的Receptor-Ligand Pharmacophore Generation模块建立,并以Screen Library模块进行优化,获得最优子药效团。最优子药效团模型由2个氢键受体、3个疏水基团以及19个排除体积组成,辨识有效性指数N值2.82、综合评价指数CAI值1.84。采用该模型对TCMD数据库进行筛选,命中5 235种化学成分、1 193种来源天然动植物,最后确定常用中药62味。专利检索得到38味常用中药,与虚拟筛选结果进行比对,最终获得7味中药。The combined application of statins that inhibit HMG-CoA reductase and fibrates that activate PPAR-α can produce a better lipid-lowering effect than the simple application, but with stronger adverse reactions at the same time. In the treatment of hyperlipidemia, the combined administration of TCMs and HMG-CoA reductase inhibitor in treating hyperlipidemia shows stable efficacy and less adverse reactions, and provides a new option for the combined application of drugs. In this article, the pharmacophore technology was used to search chemical components of TCMs, trace their source herbs, and determine the potential common TCMs that could activate PPAR-α. Because there is no hyperlipidemia-related medication reference in modern TCM classics, to ensure the high safety and efficacy of all selected TCMs, we selected TCMs that are proved to be combined with statins in the World Traditional/Natural Medicine Patent Database, analyzed corresponding drugs in pharmacophore results based on that, and finally obtained common TCMs that can be applied in PPAR-α and combined with statins. Specifically, the pharmacophore model was based on eight receptor-ligand com- plexes of PPAR-α. The Receptor-Ligand Pharmacophore Generation module in the DS program was used to build the model, optimize with the Screen Library module, and get the best sub-pharmacophore, which consisted of two hydrogen bond acceptor, three hydrophobic groups and 19 excluded volumes, with the identification effectiveness index value N of 2. 82 and the comprehensive evaluation index CAI value of 1.84. The model was used to screen the TCMD database, hit 5 235 kinds of chemical components and 1 193 natural animals and plants, and finally determine 62 TCMs. Through patent retrieval, we found 38 TCMs; After comparing with the virtual screening results, we finally got seven TCMs.

关 键 词：降血脂 药效团 虚拟筛选 专利检索 贝特类药物 药物联用 

分 类 号：R285[医药卫生—中药学]