Structural Prerequisites for Pim-1 Kinase Inhibition and the Identification of a Pyrazolyl-Methylene-Indolinone Hit
Abstract
Introduction: Pim-1 is a serine/threonine kinase of the pan-Pim family (Pim-1, -2, and -3), whose overexpression is associated with various cancers. Its distinctive hinge-region architecture provides opportunities for selective inhibitor development, with several inhibitors reported as clinical candidates. Understanding structure-activity relationships is essential for distinguishing biologically active compounds from high-scoring docking hits, a major challenge in structure-based drug discovery.
Methods: A virtual screening workflow comprising Glide docking and Induced Fit Docking (IFD) was applied to approximately 900,000 commercially available compounds. Six structurally diverse compounds were selected for in vitro Pim-1 inhibitory activity evaluation. Molecular dynamics (MD) simulations and quantum mechanical (QM) calculations were subsequently performed to investigate the structural determinants of inhibitory activity.
Results: Among the tested compounds, compound 6, representing a previously unreported pyrazolyl-methylene-indolinone scaffold for Pim-1 inhibition, was identified as a Pim-1 inhibitory hit with an IC5 0 value of 5.77 µM. QM calculations revealed differences in the energetic accessibility of coplanar geometries between the active and inactive compounds, providing a structural explanation for the discrepancy between docking predictions and experimental activity. Moreover, MD simulations of Pim-1 in complex with compound 6 revealed the formation of dual…
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