Cheminformatics-based analysis identified Novel compounds from Nelumbo nucifera as potential inhibitors targeting...

The present study investigates the in-silico identification of novel phytochemical inhibitors from N. nucifera molecularly targeting the PI3K/Akt/mTOR signalling pathway as a breast cancer chemotherapeutic agent, especially to treat PIK3CA mutant tumours. Despite huge advancements, including the application of various complex intracellular signalling pathways in oncogenesis, breast cancer remains a menace, causing significant morbidity and mortality worldwide. The efficiency of the PI3K/Akt/mTOR pathway plays a substantial part in hormone receptor-positive (HR+/HER2-) HER2-negative breast cancers, where mutations of the PIK3CA gene lead to tumour progression and are associated with therapy resistance. This study employs a range of computational approaches, including molecular docking, ADMET (absorption, distribution, metabolism, and toxicity) prediction, molecular dynamics simulations, MM-PBSA binding energy calculations, and Quantum calculations, to identify potential phytochemical inhibitors from N. nucifera. Two lead compounds, Anonaine (CID_160597) and Dehydroaporheine (CID_161899), exhibited more binding abilities towards the PI3Kα protein than the reference inhibitor buparlisib. These compounds were further studied for pharmacokinetic profile, bioactivity and toxicity, and they showed a high Drug-Likeness score. Notably, MD simulations revealed conserved interactions of these lead compounds with the PI3Kα protein, which could be promising for breast cancer therapeutic applications. This research lays the groundwork for additional experimental confirmation and underscores the promise of N. nucifera products in creating effective alternative therapies against breast cancer. This research may contribute to advancing personalised medicine approaches in oncology, offering new avenues for targeted therapies in PIK3CA-mutant breast cancer.