- 期刊
Molecular Modeling Studies of 3,6-Diaryl-7H-[1,2,4] Triazolo [3,4-B] [1,3,4] Thiadiazines As Tubulin Inhibitors Using 3D-QSAR And Molecular Docking
摘要
In this paper, a three‐dimensional quantitative structure‐activity relationships (3D-QSAR) study for 30 3,6‐diaryl‐7H‐[1,2,4]triazolo[3,4‐b][1,3,4]thiadiazine derivatives as tubulin inhibitors was established using Topomer CoMFA. The models were built based on different fragment cutting models. Finally, three groups of effective 3D‐QSAR models were obtained. The cross‐validation coefficient (q2) of the best model is 0.774, non-cross‐correlation coefficient (r2) is 0.974, correlation coefficient of external validation (Qext2) is 0.822, and standard estimation error (SEE) is 0.236. The results show that the model has good estimation stability and prediction capability. In addition, the molecular docking method was used to study the binding mode of these inhibitors and tubulin. The docking results show that the compounds can stably bind to the colchicine binding site of tubulin by forming stable hydrogen bonds with Cysβ241, Metβ250 and Tyrα344 residues. The results of this study provide effective theoretical guidance for the development of novel tubulin inhibitors. On this basis, 28 new inhibitors were designed and their inhibitory activity was predicted.