S6K2 is an important protein in mTOR signaling pathway and cancer. To identify potential S6K2 inhibitors for mTOR pathway treatment, a virtual screening of 1,575,957 active molecules was performed using PLANET, AutoDock GPU, and AutoDock Vina, with their classification abilities compared. The MM/PB(GB)SA method was used to identify four compounds with the strongest binding energies. These compounds were further investigated using molecular dynamics (MD) simulations to understand the properties of the S6K2/ligand complex. Due to a lack of available 3D structures of S6K2, OmegaFold served as a reliable 3D predictive model with higher evaluation scores in SAVES v6.0 than AlphaFold, AlphaFold2, and RoseTTAFold2. The 150 ns MD simulation revealed that the S6K2 structure in aqueous solvation experienced compression during conformational relaxation and encountered potential energy traps of about 19.6 kJ mol. The virtual screening results indicated that Lys75 and Lys99 in S6K2 are key binding sites in the binding cavity. Additionally, MD simulations revealed that the ligands remained attached to the activation cavity of S6K2. Among the compounds, compound 1 induced restrictive dissociation of S6K2 in the presence of a flexible region, compound 8 achieved strong stability through hydrogen bonding with Lys99, compound 9 caused S6K2 tightening, and the binding of compound 16 was heavily influenced by hydrophobic interactions. This study suggests that these four potential inhibitors with different mechanisms of action could provide potential therapeutic options.

中文翻译：

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计算机辅助发现和评估潜在核糖体蛋白 S6 激酶 β 2 抑制剂

S6K2是mTOR信号通路和癌症中的重要蛋白。为了识别用于 mTOR 通路治疗的潜在 S6K2 抑制剂，使用 PLANET、AutoDock GPU 和 AutoDock Vina 对 1,575,957 个活性分子进行了虚拟筛选，并比较了它们的分类能力。 MM/PB(GB)SA 方法用于鉴定具有最强结合能的四种化合物。使用分子动力学 (MD) 模拟进一步研究这些化合物，以了解 S6K2/配体复合物的特性。由于缺乏 S6K2 的可用 3D 结构，OmegaFold 作为可靠的 3D 预测模型，在 SAVES v6.0 中的评估分数高于 AlphaFold、AlphaFold2 和 RoseTTAFold2。 150 ns MD 模拟表明，水溶剂化中的 S6K2 结构在构象弛豫过程中经历了压缩，并遇到了约 19.6 kJ mol 的势能陷阱。虚拟筛选结果表明S6K2中的Lys75和Lys99是结合腔中的关键结合位点。此外，MD 模拟显示配体仍然附着在 S6K2 的激活腔上。在这些化合物中，化合物1在柔性区域存在的情况下诱导S6K2的限制性解离，化合物8通过与Lys99的氢键作用实现了很强的稳定性，化合物9导致S6K2收紧，化合物16的结合受到疏水相互作用的严重影响。这项研究表明，这四种具有不同作用机制的潜在抑制剂可以提供潜在的治疗选择。