Discovery of a novel PI3Kα inhibitor for breast cancer therapy via virtual screening method, molecular dynamics simulation and biological evaluation
Issued Date
2026-05-01
Resource Type
ISSN
10933263
eISSN
18734243
Scopus ID
2-s2.0-105027313811
Journal Title
Journal of Molecular Graphics and Modelling
Volume
144
Rights Holder(s)
SCOPUS
Bibliographic Citation
Journal of Molecular Graphics and Modelling Vol.144 (2026)
Suggested Citation
Boonma T., Nutho B., Kanjanasirirat P., Rajchakom C., Nunthaboot N. Discovery of a novel PI3Kα inhibitor for breast cancer therapy via virtual screening method, molecular dynamics simulation and biological evaluation. Journal of Molecular Graphics and Modelling Vol.144 (2026). doi:10.1016/j.jmgm.2026.109289 Retrieved from: https://repository.li.mahidol.ac.th/handle/123456789/114446
Title
Discovery of a novel PI3Kα inhibitor for breast cancer therapy via virtual screening method, molecular dynamics simulation and biological evaluation
Author's Affiliation
Corresponding Author(s)
Other Contributor(s)
Abstract
Phosphatidylinositol-4,5-bisphosphate 3-kinase alpha (PI3Kα) is a central signaling enzyme driving cell proliferation and growth in cancers including breast cancer. Selective inhibition of PI3Kα isoform has become a promising therapeutic approach. In this work, 2000 in-house natural compounds were virtually screened against the ATP-binding site of PI3Kα. Of these, 618 compounds were predicted to have acceptable drug-likeness, pharmacokinetic, and toxicity properties based on in silico ADMET screening. Docking analysis highlighted four candidates forming stable hydrogen bonds with key residues V851, S854, and Q859 in the PI3Kα binding pocket. Molecular dynamics simulations were then used to assess their structural features and dynamic stability. Hit 2 was found to form strong hydrogen bonds with E849 and V851 of the PI3Kα protein. MM/GBSA-based binding free energy analysis supported that Hit 2 possessed the most favorable binding affinity to PI3Kα among the identified candidates. In vitro cytotoxicity assays were then performed in MCF-7 and MDA-MB-231 breast cancer cell lines, with alpelisib as a reference compound. Hit 2 reduced cell viability in both cell lines, but its effect was particularly pronounced in MDA-MB-231 cells, a model of triple-negative breast cancer (TNBC). These results suggest that Hit 2 represents a promising natural scaffold for further design and development in breast cancer therapy, with particular relevance for aggressive TNBC.