Qingyan Zhang, Feng Sang, Jieyu Qian, ShaoLi Lyu, Wang Wang, Ying Wang, Qiang Li, LinFang Du
Journal of biomolecular structure & dynamics 2021 JulPhosphatidylinositol 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.
Qingyan Zhang, Feng Sang, Jieyu Qian, ShaoLi Lyu, Wang Wang, Ying Wang, Qiang Li, LinFang Du. Identification of novel potential PI3Kα inhibitors for cancer therapy. Journal of biomolecular structure & dynamics. 2021 Jul;39(10):3721-3732
PMID: 32425109
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