Résumé
Proviral integration Moloney virus (PIM) 1, 2, and 3 kinases are a family of constitutively active serine/threonine kinases that are involved in a number of signaling pathways important to cancer cells. Their overexpression in a variety of human hematopoietic malignancies and solid tumors suggest that inhibition of PIM signaling could provide patients with therapeutic benefit. In this study, a series of 3,5-disubstituted indole derivatives have been systematically studied using three-dimensional quantitative structure-activity relationship (3D−QSAR) analysis, molecular docking simulation, and partial least-squares (PLS) analysis methods to explore the influence of the structural characteristics on the inhibitory activity and use them to propose novel bioactive molecules. The comparative molecular field and comparative molecular similarity indices analyses (CoMFA and CoMSIA) models exhibited a good correlation between the predicted and experimental activities with excellent predictive capability and yielded statistically reliable value (CoMFA: Q2 = 0.535, R2 = 0.987, r2pred = 0.909; CoMSIA: Q2 = 0.785, R2 = 0.989, r2pred = 0.969). Based on the CoMFA and CoMSIA models and docking results, ten novel potent PIM-1 inhibitors (N1–N10) have been designed and the molecular models have validated their inhibitory activities. These results provided strong theoretical guidance for the development of novel PIM-1 inhibitors.
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•3D-QSAR study of 3,5-disubstituted indole derivatives as PIM-1 kinase inhibitors was reported.•New potent PIM-1 kinase inhibitors were designed based on the CoMFA and CoMSIA models.•Molecular docking studies validated the results of 3D-QSAR.•Reported results are valuable for designing novel PIM-1 kinase inhibitors.