Discovery of a Selective PI3K Inhibitor through Structure-Based Docking and Multilevel In Silico Validation

Phosphoinositide 3-kinase (PI3K) represents a pivotal therapeutic target implicated in cellular proliferation, metabolic processes, and oncogenic mechanisms. This research delineates a comprehensive in silico methodology aimed at identifying effective and pharmacokinetically favorable inhibitors of PI3K. Structure-based molecular docking was executed targeting the ATP-binding pocket of PI3K, revealing that the highest-ranked compound, MOL ID: 11325, demonstrated a significant binding affinity, reflected by a docking score of –8.558 kcal/mol.
ADMET and SwissADME profiling confirmed that molecule 11325 is Lipinski-compliant, P-gp non-substrate, has a bioavailability score of 0.55, no PAINS or Brenk alerts, and a favorable synthetic accessibility (2.68), supporting its drug-likeness and development potential.. A 100 ns molecular dynamics simulation confirmed the stability of the PI3K–ligand complex, demonstrating minimal deviations in root mean square deviation (RMSD) and root mean square fluctuation (RMSF). The binding free energy, determined through the MMGBSA method, exhibited a favorable value (ΔG_bind ≈ –58.6 kcal/mol), thereby corroborating the ligand's affinity. The FEL analysis revealed distinct low-energy states, while the PCA indicated minimal structural fluctuations, confirming a stable and specific binding mode. Molecule 11325 was designated as a novel, drug-like, and dynamically stable PI3K inhibitor by this integrated computational approach, indicating that it requires additional preclinical validation for therapeutic development.