基于Topomer CoMFA的苯磺酰基亚胺噻唑衍生物的三维定量构效关系研究和分子设计

采用Topomer CoMFA方法对21个苯磺酰基亚胺噻唑衍生物进行三维定量构效关系研究,得到了HIV-1非核苷类逆转录酶抑制剂的3D-QSAR模型,其拟合复相关系数r2=0.964,交互验证复相关系数q2=0.801,外部验证复相关系数Qext2=0.959;采用基于片段的药物设计方法 Topomer Search从ZINC数据库中虚拟筛选出3个Ra基团和7个Rb基团,且设计得到21个新化合物.结果表明:该模型不仅稳定性良好,而且具有较强的预测能力;采用Topomer Search技术能够有效的筛选进而设计出新的化合物,为抗艾滋病新药的设计提供理论依据.

3D-QSAR studies of thiazolidenebenzenesulfonamide derivatives based on Topomer CoMFA method and molecular design

The three-dimensional quantitative structures-activity relationship (3D-QSAR) models were developed from a data set of 21 thiazolidenebenzenesulfonamide derivatives by using Topomer comparative molecular field analysis (Topomer CoMFA) method. The best Topomer CoMFA model had a cross-validation q2 value of 0.964, a non cross-validation r2 value of 0.801 and an external validation statistic Qext2 value of 0.959. The study also used the methodology of fragment-based drug design (FBDD) to virtual screen new moleculars by using Topomer Search technology. The obtained 3 Ra groups and 7 Rb groups with the highest contribution values were searched from ZINC database, and 21 new moleculars with effective high activities were designed. It is demonstrated that Topomer CoMFA model had good stability and predictive ability. Topomer Search technology could be effectively used to screen and design new compound, which provided the basis for the design of new anti-AIDS drugs.