School of Pharmaceutical Sciences, Jiangnan University, Wuxi, 214122, Jiangsu, China.
Institute of Bioinformatics and Medical Engineering, School of Electrical and Information Engineering, Jiangsu University of Technology, Changzhou, 213001, China.
J Mol Model. 2019 Jul 23;25(8):242. doi: 10.1007/s00894-019-4129-x.
Phosphoinositide 3-kinases (PI3Ks) are crucial for cell proliferation, metabolism, motility, and cancer progression. Since the selective PI3Kδ inhibitor, idelalisib, was firstly approved by the FDA in 2014, large numbers of selective PI3Kδ inhibitors have been reported, but the detailed mechanisms of selective inhibition to PI3Kδ for idelalisib or its derivatives have not been well addressed. In this study, 3D-QSAR with COMFA, molecular docking, and molecular dynamic (MD) simulations was used to explore the binding modes between PI3Kδ and idelalisib derivatives. Firstly, a reliable COMFA model (q = 0.59, ONC = 8, r = 0.966) was built and the contour maps showed that the electrostatic field had more significant contribution to the bioactivities of inhibitors. Secondly, two molecular docking methods including rigid receptor docking (RRD) and induced fit docking (IFD) were employed to predict the docking poses of all the studied inhibitors and revealed the selective binding mechanisms. And then, the results of the MD simulation and the binding free energy decomposition verified that the binding of PI3Kδ/inhibitors was mainly contributed from hydrogen bonding and hydrophobic interactions and some key residues for selective binding were highlighted. Finally, based on the models developed, 14 novel inhibitors were optimized and some showed satisfactory predicted bioactivity. Taken together, the results provided by this study may facilitate the rational design of novel and selective PI3Kδ inhibitors. Graphical abstract .
磷酸肌醇 3-激酶（PI3Ks）对于细胞增殖、代谢、运动和癌症进展至关重要。自 2014 年 FDA 首次批准选择性 PI3Kδ 抑制剂idelalisib 以来，已经报道了大量的选择性 PI3Kδ 抑制剂，但 idelalisib 或其衍生物对 PI3Kδ 的选择性抑制的详细机制尚未得到很好的解决。在这项研究中，我们使用 3D-QSAR 与 COMFA、分子对接和分子动力学（MD）模拟来探索 PI3Kδ 与 idelalisib 衍生物之间的结合模式。首先，构建了一个可靠的 COMFA 模型（q = 0.59，ONC = 8，r = 0.966），并通过轮廓图显示静电场对抑制剂的生物活性有更显著的贡献。其次，采用两种分子对接方法，包括刚性受体对接（RRD）和诱导契合对接（IFD），预测了所有研究抑制剂的对接构象，揭示了选择性结合的机制。然后，通过 MD 模拟的结果和结合自由能分解，验证了 PI3Kδ/抑制剂的结合主要来自氢键和疏水相互作用，突出了一些用于选择性结合的关键残基。最后，基于所建立的模型，对 14 种新型抑制剂进行了优化，其中一些表现出令人满意的预测生物活性。总之，本研究的结果可能有助于合理设计新型和选择性 PI3Kδ 抑制剂。
