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Discovery of a natural PI3Kδ inhibitor through virtual screening and biological assay study

Guo, Jun-Fang, Ning, Zhong-Qi, Wu, Xia, Qiao, Yan-Jiang, Wang, Xing
Biochemical and biophysical research communications 2019 v.508 no.3 pp. 709-714
Oriental traditional medicine, active ingredients, amino acids, asthma, beta-N-acetylhexosaminidase, bioassays, computer simulation, drugs, enzyme inhibition, immunoglobulin E, inhibitory concentration 50, mast cells, models, pharmacology, screening
Phosphoinositide-3-kinase-δ (PI3Kδ) is a key regulator in the process of IgE mediated mast cell degranulation, which directly induces allergic diseases, such as asthma. This study is aimed at discovery of natural PI3Kδ inhibitors from Chinese medicine and evaluating their anti-mast cell degranulation activity. A combined virtual screening based on 3D pharmacophore model and molecular docking was used to screen for bioactive ingredients directly targeting PI3Kδ. Then, an in vitro kinase inhibition assay was conducted to evaluate the PI3Kδ inhibitory activity of the virtual screening hits. Subsequently, a β-hexosaminidase release assay was performed to verify the anti-mast cell degranulation activity of the active compounds. Finally, ginkgoneolic acid was identified as a PI3Kδ inhibitor (IC50 = 2.49 μM) and exhibited anti-mast cell degranulation activity in vitro (IC50 = 2.40 μM). Docking studies showed that Glu826, Val827 and Val828 were key amino acid residues for PI3Kδ inhibitory activity. Ginkgoneolic acid may be a potential lead compound for developing effective and safe PI3Kδ-inhibiting drugs.