3D- and 2D-QSAR models’ study and molecular docking of novel nitrogen-mustard compounds for osteosarcoma

Background: The dipeptide-alkylated nitrogen-mustard compound is a new kind of nitrogen-mustard derivative with a strong anti-tumor activity, which can be used as a potential anti-osteosarcoma chemotherapy drug. Objective: 2D- and 3D-QSAR (structure–activity relationship quantification) models were established to predict the anti-tumor activity of dipeptide-alkylated nitrogen-mustard compounds. Method: In this study, a linear model was established using a heuristic method (HM) and a non-linear model was established using the gene expression programming (GEP) algorithm, but there were more limitations in the 2D model, so a 3D-QSAR model was introduced and established through the CoMSIA method. Finally, a series of new dipeptide-alkylated nitrogen-mustard compounds were redesigned using the 3D-QSAR model; docking experiments were carried out on several compounds with the highest activity against tumors. Result: The 2D- and 3D-QSAR models obtained in this experiment were satisfactory. A linear model with six descriptors was obtained in this experiment using the HM through CODESSA software, where the descriptor “Min electroph react index for a C atom” has the greatest effect on the compound activity; a reliable non-linear model was obtained using the GEP algorithm model (the best model was generated in the 89th generation cycle, with a correlation coefficient of 0.95 and 0.87 for the training and test set, respectively, and a mean error of 0.02 and 0.06, respectively). Finally, 200 new compounds were designed by combining the contour plots of the CoMSIA model with each other, together with the descriptors in the 2D-QSAR, among which compound I1.10 had a high anti-tumor and docking ability. Conclusion: Through the model established in this study, the factors influencing the anti-tumor activity of dipeptide-alkylated nitrogen-thaliana compounds were revealed, providing direction and guidance for the further design of efficient chemotherapy drugs against osteosarcoma.