In Silico Studies of Piperidine Derivatives as Protein Kinase B Inhibitors through 3D-QSAR, Molecular Docking and Molecular Dynamics Simulation

Background: Protein kinase B (Akt) is a serine/threonine-protein kinase that drives the diverse physiological process. Akt is a promising therapeutic target, which involves cancer cell growth, survival, proliferation and metabolism. Objective: The study aims to design highly active Akt inhibitors, and to elucidate the structural requirements for their biological activity, we analyzed the key binding features and summarized the structural determinants for their bioactivities. Methods: A series of piperidine derivatives have been investigated employing three-dimensional quantitative structure-activity relationship (3D-QSAR), molecular docking and molecular dynamics simulation. Results: The statistics of the comparative molecular field analysis (CoMFA) model (Q²=0.631, R²=0.951) and the comparative molecular similarity index analysis (CoMSIA) model (Q²=0.663, R²=0.966) indicated that our 3D-QSAR model was accurate and reliable. Besides, the stability of receptor-ligand interactions under physiological conditions was then evaluated by molecular dynamics simulation, in agreement with the molecular docking results. Conclusion: Our study provided valuable insights for the discovery of potent Akt inhibitors.