In Silico Identification of Lepiotaprocerin C as a Promising PIM-1 Kinase Inhibitor: An Integrated Docking, Molecular Dynamics, MM/PBSA, QSAR, and ADMET Study.

Abstract

Proviral Integration site for Moloney murine leukemia virus-1 (PIM-1) kinase, a serine/threonine kinase overexpressed in various malignancies, plays a critical role in promoting cell survival and proliferation, making it a promising target for anticancer therapy. This study employed an integrated in silico approach to evaluate Lepiotaprocerin derivatives (A to L) from Macrolepiota procera as potential PIM-1 inhibitors. Molecular docking of 12 Lepiotaprocerins revealed Lepiotaprocerin C as the most potent compound, exhibiting superior binding affinity (-11.4 kcal/mol) compared with the reference inhibitor AZD1208. Binding site validation using CASTp, PrankWeb, and blind docking confirmed the ATP-binding pocket as the active cavity. The Lepiotaprocerin C-PIM-1 complex demonstrated enhanced stability during 200 ns molecular dynamics simulations, maintaining low RMSD and strong hydrogen-bond interactions, supported by a favorable Molecular Mechanics/Poisson-Boltzmann Surface Area (MM/PBSA) binding free energy (-22.0 ± 2.1 kcal/mol). Based on quantitative structure activity relationship (QSAR) analysis, the calculated pIC₅₀ value of Lepiotaprocerin C was 8.67. QSAR modeling (R ² = .74, Q ² = 0.90) confirmed robust predictive capacity, while absorption, distribution, metabolism, and elimination and PerMM analysis indicated favorable pharmacokinetic and permeability profiles. Prediction of Activity Spectra for Substances and toxicity predictions further revealed high antineoplastic potential (Pa = 0.881) and a nontoxic safety profile. These results highlight Lepiotaprocerin C as a promising, stable, and safe inhibitor of PIM-1 kinase, warranting further in vitro and in vivo validation for potential anticancer drug development.