Background: Phosphoinositide-3 kinases (PI3Ks) are key signaling molecules that affect a diverse array of biological processes in cells, including proliferation, differentiation, survival, and metabolism. The abnormal activity of PI3K signals is closely related to the occurrence of many diseases, which has become a very promising drug target, especially for the treatment of cancer. PI3Kδ/γ inhibitors can reduce toxicity concerns for chronic indications such as asthma and rheumatoid arthritis compared with pan PI3Ks inhibitors.
Methods: With the aim of finding more effective PI3Kδ/γ dual inhibitors, virtual screening, ADMET prediction Molecular Dynamics (MD) simulations and MM-GBSA were executed based on the known p110δ/γ crystal structure. Compound ZINC28564067 with high docking score and low toxicity was obtained.
Results: By MD simulations and MM-GBSA, we could observe that ZINC28564067 had more favorable conformation binding to the PI3Kδ/γ than the original ligands.
Conclusion: The results provided a rapid approach for the discovery of novel PI3Kδ/γ dual inhibitors which might be a potential anti-tumor lead compound.