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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 (IC 50 = 2.49 μM) and exhibited anti-mast cell degranulation activity in vitro (IC 50 = 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. Graphical abstract Image 1 Highlights • Ginkgoneolic acid derived from TCM was identified as a PI3Kδ inhibitor with IC 50 of 2.49μM. • Ginkgoneolic acid significantly inhibited degranulation of mast cellswith an IC 50 of 2.40μM. • The inhibition of ginkgoneolic acid on PI3Kδ was revealed by interacting with residues such as Glu826, Val827 and Val828. [ABSTRACT FROM AUTHOR]