LAUSR

Abstract Phosphatidylinositol 3-kinase alpha (PI3Kα) is among the most important PI3K isoforms and has been associated with multiple human cancers. Therefore, PI3Kα has garnered considerable attention as a viable target for anticancer drug discovery, and thus the identification and development of highly potent inhibitors of this isoform has become an important line of research. Here, structure-based virtual screening, bioassays, and molecular dynamics simulations were performed to discover novel potential PI3Kα inhibitors. TCM-N1 (ZINC13382850) was identified as a possible PI3Kα inhibitor. Particularly, fluorescence quenching assays determined that the binding affinity of the aforementioned compound was superior to that of a reference ligand (BYL719; i.e. a known PI3Kα inhibitor). Moreover, enzymatic activity and cell proliferation inhibition assays indicated that TCM-N1 possessed a moderate inhibition activity against PI3Kα and a relatively high anti-tumor proliferation ability in gastric, colorectal, and cervical cancer cells. The binding model and related thermodynamic parameters further demonstrated that TCM-N1 was tightly embedded into the ATP-binding pocket via hydrogen bonds, van der Waals interactions, and hydrophobic interactions. Therefore, this study provides promising insights into the development and design of more potent PI3Kα-inhibiting analogs. Communicated by Ramaswamy H. Sarma