School of Pharmaceutical Sciences, Jiangnan University, Wuxi, China.
Institute of Bioinformatics and Medical Engineering, School of Electrical and Information Engineering, Jiangsu University of Technology, Changzhou, China.
Chem Biol Drug Des. 2021 Jun;97(6):1158-1169. doi: 10.1111/cbdd.13838. Epub 2021 Mar 13.
Phosphatidylinositol-3-kinase (PI3K) is important for cell proliferation, differentiation, and apoptosis, and the diverse physiological roles of different PI3K isoforms have highlighted the significance of the development of PI3Kδ inhibitors. A large number of PI3Kδ inhibitors have been reported after the FDA approval of Idelalisib, but the clinical use of Idelalisib was limited because of its serious side effects. Therefore, great efforts have been made on the development of PI3Kδ inhibitors with higher selectivity and lower toxicity, but there is no new PI3Kδ inhibitor coming into the market so far. Even so, as the first listed PI3K inhibitor, Idelalisib could be used as an effective tool to investigate the selective inhibition mechanism of PI3Kδ. Thus, in this study, a modeling strategy integrated 3D-QSAR, pharmacophore model, and molecular dynamics simulation was employed to reveal the key chemical characteristics of Idelalisib analogs and the binding pattern between the inhibitors and PI3Kδ. First, the CoMFA model with high statistical significance was built to reveal the general structure-activity relationships. And then, a reliable pharmacophore model with a robust discrimination capability was constructed to expound the main chemical characteristics of the PI3Kδ inhibitors. Finally, molecular dynamics simulation was conducted to explore the binding modes and some key residues refer to δ-selective binding were highlighted with binding-free energy calculation. In summary, these models and results would provide some effective help for the discovery or the rational design of novel PI3Kδ inhibitors.
磷脂酰肌醇-3-激酶（PI3K）对于细胞增殖、分化和凋亡非常重要，不同 PI3K 同工型的多种生理作用突显了开发 PI3Kδ 抑制剂的重要性。在 FDA 批准伊德拉利昔布后，已经报道了大量的 PI3Kδ 抑制剂，但由于其严重的副作用，伊德拉利昔布的临床应用受到限制。因此，人们在开发具有更高选择性和更低毒性的 PI3Kδ 抑制剂方面做出了巨大努力，但迄今为止还没有新的 PI3Kδ 抑制剂进入市场。即便如此，作为第一个上市的 PI3K 抑制剂，伊德拉利昔布可用作研究 PI3Kδ 选择性抑制机制的有效工具。因此，在本研究中，采用了整合 3D-QSAR、药效团模型和分子动力学模拟的建模策略，以揭示伊德拉利昔布类似物的关键化学特征以及抑制剂与 PI3Kδ 之间的结合模式。首先，构建了具有高统计显著性的 CoMFA 模型，以揭示一般的构效关系。然后，构建了一个可靠的具有强大区分能力的药效团模型，以阐述 PI3Kδ 抑制剂的主要化学特征。最后，进行了分子动力学模拟，以探索结合模式，并通过结合自由能计算突出了一些与 δ 选择性结合相关的关键残基。总之，这些模型和结果将为新型 PI3Kδ 抑制剂的发现或合理设计提供一些有效的帮助。
