2. Academic Validation
  3. Discovery of a natural PI3Kδ inhibitor through virtual screening and biological assay study

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

  • Biochem Biophys Res Commun. 2019 Jan 15;508(3):709-714. doi: 10.1016/j.bbrc.2018.12.009.
Jun-Fang Guo 1,  Zhong-Qi Ning 1,  Xia Wu 2,  Yan-Jiang Qiao 3,  Xing Wang 4
Affiliations

Affiliations

  • 1 School of Traditional Chinese Medicine, Capital Medical University, Fengtai District, Beijing, 100069, PR China.
  • 2 School of Traditional Chinese Medicine, Capital Medical University, Fengtai District, Beijing, 100069, PR China; Beijing Key Laboratory of Traditional Chinese Medicine Collateral Disease Theory Research, Capital Medical University, Fengtai District, Beijing, 100069, PR China.
  • 3 Key Laboratory of TCM-information Engineer of State Administration of TCM, School of Chinese Materia Medica, Beijing University of Chinese Medicine, No.11, North San huan Road, Chaoyang District, Beijing, 100029, PR China. Electronic address: yjqiao@263.net.
  • 4 School of Traditional Chinese Medicine, Capital Medical University, Fengtai District, Beijing, 100069, PR China; Beijing Key Laboratory of Traditional Chinese Medicine Collateral Disease Theory Research, Capital Medical University, Fengtai District, Beijing, 100069, PR China. Electronic address: kingstar1016@sina.com.
PMID: 30528237 DOI: 10.1016/j.bbrc.2018.12.009
Abstract

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.

Keywords

Ginkgoneolic acid; Mast cell degranulation; Phosphoinositide-3-kinase-δ; Virtual screening.

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