Unlocking Safer Pi3kα Inhibition: In Silico Discovery of a Safer Alpelisib-Derived Lead Compound

Colorectal cancer (CRC) is a leading cause of cancer-related mortality worldwide, with the PI3K/AKT signaling pathway playing a crucial role in its progression, making it an important therapeutic target. In this study, novel analogues of Alpelisib were designed and evaluated using an integrated computational approach to identify safer and more effective PI3K inhibitors. The PI3Kα protein was identified using the KEGG database, followed by structural modeling and active site analysis using UniProtKB and PyMOL. The designed analogues were optimized and assessed for drug-likeness based on Lipinski’s and Veber’s rules. ADMET properties were predicted, and molecular docking studies were performed to evaluate binding affinity and interaction profiles. Among the compounds, Compound 5 exhibited the highest binding affinity but showed higher toxicity, whereas Compound 4 demonstrated strong binding interactions with comparatively lower toxicity. Therefore, Compound 4 is proposed as a promising lead candidate for further experimental validation.