Ribosomal protein S6 kinase beta-1 (S6K1) is an attractive therapeutic target. In this study, computational analysis of five thiophene urea-based S6K1 inhibitors was performed. Molecular docking showed that the five compounds formed hydrogen bonds with residues Glu173 and Leu175 of S6K1 and hydrophobic interactions with residues Val105, Leu97 and Met225, and these interactions were key elements for the inhibitory potency of the compounds. Binding free energy (ΔG_bind) decomposition analysis showed that Leu97, Glu173, Val 105, Leu175, Leu97 and Met225 contribute the most to ΔG_bind. Based on the computer results, phenylpyrazole based amides (D1–D3) were designed and synthesized. Biological evaluation revealed that D2 exhibited 15.9 nM S6K1 inhibition, medium microsomal stability and desirable bioavailability.

中文翻译：

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计算机辅助发现基于苯基吡唑的酰胺作为有效的 S6K1 抑制剂

核糖体蛋白 S6 激酶 beta-1 (S6K1) 是一个有吸引力的治疗靶点。在这项研究中，对五种噻吩脲基 S6K1 抑制剂进行了计算分析。分子对接表明这五种化合物与S6K1的Glu173和Leu175残基形成氢键，并与Val105、Leu97和Met225残基形成疏水相互作用，这些相互作用是化合物抑制效力的关键因素。结合自由能 (Δ G _bind ) 分解分析表明 Leu97、Glu173、Val 105、Leu175、Leu97 和 Met225 对 Δ G _bind贡献最大。基于计算机结果，设计并合成了基于苯基吡唑的酰胺（ D1-D3 ）。生物学评价表明D2表现出 15.9 nM S6K1 抑制、中等微粒体稳定性和理想的生物利用度。