红景天苷及其类似物抗缺氧药效团模型的构建及可靠性验证

Construction and reliability validation of anti-hypoxic pharmacophore model of salidroside and its analogues

目的构建红景天苷及其类似物抗缺氧药效团模型,为红景天苷类似物的结构优化提供理论依据。方法搜集实验室前期合成的具有抗缺氧活性的红景天苷类似物,分析相对活性,构建小分子数据库,进行构象搜索;选择红景天苷和数据库中活性最好的2个化合物作为模板分子,将其最低能量构象叠合后保留最佳叠合模式,识别药效特征基团并构建药效团模型。检索文献报道具有抗缺氧活性的红景天苷类似物,构建小分子数据库,进行构象分析。基于药效团模型对两个小分子构象库进行验证性搜索,验证其可靠性。结果构建红景天苷及其类似物小分子数据库Salidroside Analogue-MDB,包含129个化合物,得到小分子构象库Salidroside Analogue-CDB;选择红景天苷、LN-22和CH-1为模板分子,构建了一个五点药效团模型;在Salidroside Analogue-CDB进行验证性搜索,检出率为100%。构建红景天苷类似物S01、N03和SalA-4g构象库SNS-CDB,进行验证性搜索,3个化合物都命中。结论构建的红景天苷及其类似物抗缺氧五点药效团模型比较可靠,可为后续研究提供一定理论支撑。

Objective To construct an anti-hypoxic pharmacophore model for salidroside and its analogs,so as to provide a theoretical basis for the structural optimization of salidroside analogs.Methods The salidroside analogues with anti-hypoxic activity synthesized in the laboratory were collected for analysis of their relative activities and construction of a small molecule database to conduct conformational searches.Salidroside and the two compounds with the best activity in the database were selected as template molecules,and the best stacking pattern was retained after stacking their lowest energy conformations,for identifying the pharmacophores and constructing a pharmacophore model.The literature on salidroside analogs with anti-hypoxic activity was retrieved for construction of a small molecule database to conduct conformational analysis.The reliability of the two small molecule conformational libraries was validated via validation search based on the pharmacophore model.Results A small molecule database of salidroside and its analogs,Salidroside Analogue-MDB,containing 129 compounds was constructed to obtain a small molecule conformational library,Salidroside Analogue-CDB.A five-point pharmacophore model was constructed with salidroside,LN-22 and CH-1 as template molecules.The detection rate was 100%for the validation search in Salidroside Analogue-CDB.All the three salidroside analogs S01,N03 and SalA-4g were detected in their constructed conformational library SNS-CDB through validation search.Conclusion The constructed five-point anti-hypoxic pharmacophore model for salidroside and its analogs is relatively reliable,which provides certain theoretical support for subsequent studies.