Construction of Quantitative Structure Activity Relationship (QSAR) Models to Predict Potency of Structurally...

Janus kinase 2 (JAK2) inhibitors represent a promising therapeutic class of anticancer agents against many myeloproliferative disorders. Bioactivity data on pIC 50 of 2229 JAK2 inhibitors were employed in the construction of quantitative structure-activity relationship (QSAR) models. The models were built from 100 data splits using decision tree (DT), support vector machine (SVM), deep neural network (DNN) and random forest (RF). The predictive power of RF models were assessed via 10-fold cross validation, which afforded excellent predictive performance with R 2 and RMSE of 0.74 ± 0.05 and 0.63 ± 0.05, respectively. Moreover, test set has excellent performance of R 2 (0.75 ± 0.03) and RMSE (0.62 ± 0.04). In addition, Y-scrambling was utilized to evaluate the possibility of chance correlation of the predictive model. A thorough analysis of the substructure fingerprint count was conducted to provide insights on the inhibitory properties of JAK2 inhibitors. Molecular cluster analysis revealed that pyrazine scaffolds have nanomolar potency against JAK2.