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.

背景：Phosphoinositide-3激酶（PI3Ks）是关键的信号分子，影响细胞中多种生物过程，包括增殖，分化，存活和代谢。PI3K信号的异常活性与许多疾病的发生密切相关，这已成为非常有希望的药物靶标，特别是对于癌症的治疗。与泛型PI3Ks抑制剂相比，PI3Kδ/γ抑制剂可减少对哮喘和类风湿关节炎等慢性疾病的毒性担忧。

方法：为了找到更有效的PI3Kδ/γ双重抑制剂，基于已知的p110δ/γ晶体结构进行了虚拟筛选，ADMET预测分子动力学（MD）模拟和MM-GBSA。获得了对接分数高，毒性低的化合物ZINC28564067。

结果：通过MD模拟和MM-GBSA，我们可以观察到ZINC28564067与PI3Kδ/γ的结合比原始配体更有利。

结论：该结果为发现新型PI3Kδ/γ双重抑制剂提供了一种快速途径，该抑制剂可能是潜在的抗肿瘤先导化合物。