In silico design and ADMET evaluation of new inhibitors for PIM1 kinase using QSAR studies, molecular docking, and molecular dynamic simulation.

The proviral Integration site of Moloney (PIM) kinase is highly expressed in various diseases, including cancer, making the development of selective inhibitors for this protein important. A series of PIM1 inhibitors, triazolo [4, 3-b] pyridazin-3-yl-quinoline derivatives, have been studied to design new inhibitors. The activity and structural features of these derivatives were investigated to understand their interactions with PIM1 using molecular docking, molecular dynamic simulation, and QSAR techniques. In a study of 30 compounds using the structure-activity technique and the MLR method, a linear model with R  = 0.91 and R  = 0.96 was obtained. The model utilized descriptors such as RDF080v, RDF105v, RDF135v, Mor03v, and H046 to express the structural characteristics of the inhibitors. To enhance the model, the SVR non-linear method with the RBF function was also used, resulting in an improved model with R  = 0.98 and R  = 0.98. Furthermore, the molecular docking technique was employed to investigate the interaction of compounds with high (compound 25) and low (compound 13) inhibitory activity. It was observed that the rings with nitrogen atoms interacted with the protein. The molecular binding results indicate that groups such as OMe and rings with Nitrogen can enhance the inhibitory activity of the compounds. Additionally, oxygen and nitrogen atoms contribute to an increased number of hydrogen bonds, thereby increasing the inhibitory activity of the compounds. Additionally, the stability and bonding modes of active and inactive compounds were studied using molecular dynamic simulation. Based on the results, four new inhibitors were designed, demonstrating better inhibition efficiency with the PIM1 kinase compared to the reference compounds. Moreover, the designed compounds underwent evaluation for ADMET, yielding promising results.