Combining machine learning and structure-based approaches to develop oncogene PIM kinase inhibitors

Introduction: PIM kinases are targets for therapeutic intervention since they are associated with a number of malignancies by boosting cell survival and proliferation. Over the past years, the rate of new PIM inhibitors discovery has increased significantly, however, new generation of potent molecules with the right pharmacologic profiles were in demand that can probably lead to the development of Pim kinase inhibitors that are effective against human cancer. Method: In the current study, a machine learning and structure based approaches were used to generate novel and effective chemical therapeutics for PIM-1 kinase. Four different machine learning methods, namely, support vector machine, random forest, k-nearest neighbour and XGBoost have been used for the development of models. Total, 54 Descriptors have been selected using the Boruta method. Results: SVM, Random Forest and XGBoost shows better performance as compared to k-NN. An ensemble approach was implemented and, finally, four potential molecules (CHEMBL303779, CHEMBL690270, MHC07198, and CHEMBL748285) were found to be effective for the modulation of PIM-1 activity. Molecular docking and molecular dynamic simulation corroborated the potentiality of the selected molecules. The molecular dynamics (MD) simulation study indicated the stability between protein and ligands. Discussion: Our findings suggest that the selected models are robust and can be potentially useful for facilitating the discovery against PIM kinase.