3D-QSAR and molecular fragment replacement study on diaminopyrimidine and pyrrolotriazine ALK inhibitors

摘要: Abstract Over expression of anaplastic lymphoma kinase (ALK) has been found in many types cancer, and ALK is a promising therapeutic target for the treatment cancer. To obtain new potent inhibitors ALK, we conducted lead optimization using 3D-QSAR modeling molecular docking investigation 2,4-diaminopyrimidines 2,7-disubstituted-pyrrolo[2,1-f][1,2,4]triazine-based compounds. Three favorable models (CoMFA with q2, 0.555; r2, 0.939; CoMSIA 0.625; 0.974; Topomer CoMFA 0.557; r2 0.756) have developed to predict biological activity novel Search was utilized virtual screening suitable fragments. The compounds generated by fragment replacement (MFR) were evaluated prediction, Glide (docking) further prediction. 25 2,7-disubstituted-pyrrolo[2,1-f][1,2,4]triazine derivatives as potential finally obtained. In this paper, combination CoMFA, could fragments optimization. work flow which comprised modeling, Search, MFR, evaluating criteria be applied de novo drug design resulted initiate us optimize inhibitors.