Turning down PI3K/AKT/mTOR signalling pathway by natural products: an in silico multi-target approach

The PI3K/AKT/mTOR pathway is a significant target for cancer drug discovery. Many efforts have focused on discovering new inhibitors against key kinase proteins involved in this pathway for cancer treatment. PI3K/mTOR dual inhibitors, such as PKI-179, have been reported to be more effective than agents that act only on a single protein target. The present computational study aimed to discover triple target inhibitors against PI3K, AKT, and mTOR proteins. Accordingly, the PI3K protein bound with the ligand was used as input for e-pharmacophore modelling to generate the pharmacophore hypothesis and then screened for a library of 270,540 natural products from the Zinc database resulting in 57,220 compounds that matched the hypothesis. These compounds were then docked into the active site of PI3K, resulting in 292 compounds with better docking scores than the co-crystallized ligand. These compounds were re-docked into AKT and mTOR proteins. Besides, MM-GBSA binding free energy calculations, MD simulations, and ADMET prediction were carried out, leading to 5 potential triple-target inhibitors namely, ZINC000014644152, ZINC000014760695, ZINC000014644839, ZINC000095099451, and ZINC000005998557. In conclusion, these inhibitors may be possible leads for inhibiting PI3K/AKT/mTOR pathway, and they may be further evaluated in vitro and clinically as anticancer agents.