In Search of PI3K Inhibitors as Anticancer Agents: Molecular Modelling Through Virtual Screening, ADMET, and Molecular Dynamics Simulations

Abstract Cancer remains one of the leading causes of death worldwide, with current therapies often limited by side effects, recurrence of metastatic cancer, and poor patient compliance. The urgent need for new anticancer agents with novel mechanisms of action has made phosphoinositide 3‐kinase (PI3K) a promising target due to its role in cell growth, proliferation, and survival. In this study, we employed a comprehensive computational approach, beginning with the generation of a 3D pharmacophore model of PI3K using atomic property field (APF) alignment of two crystal structures (PDB IDs: 4L23 and 8TSC). Virtual screening of 2,500 MolScreen ligands and 2,431,025 ChEMBL ligands was performed, identifying 350 ligands with promising interactions with PI3K. ADMET analysis and docking scores were calculated for these, and 200 ligands showed favorable pharmacokinetic or drug‐like properties. Among them, CHEMBL2163908 emerged as the top candidate, exhibiting the highest docking score and promising drug‐likeness properties. Further molecular dynamics (MD) simulations of CHEMBL2163908 for 200 ns confirmed its stable binding at the PI3K active site. These findings highlight CHEMBL2163908 as a potential lead for the development of novel PI3K inhibitors in anticancer therapy.