Yin Yan, Sun Yuxing, Zhao Lianhua, Pan Jinpeng, Feng Yangbo
School of Chemical and Environmental Engineering , Shanghai Institute of Technology , 100 Hai Quan Rd. , Shanghai , 201418 , P. R. China . Email:
Medicinal Chemistry , The Scripps Research Institute , 130 Scripps Way , Jupiter , Florida 33458 , USA.
RSC Med Chem. 2020 Apr 30;11(5):583-590. doi: 10.1039/c9md00537d. eCollection 2020 May 1.
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 (Δ ) decomposition analysis showed that Leu97, Glu173, Val 105, Leu175, Leu97 and Met225 contribute the most to Δ . Based on the computer results, phenylpyrazole based amides () were designed and synthesized. Biological evaluation revealed that exhibited 15.9 nM S6K1 inhibition, medium microsomal stability and desirable bioavailability.
核糖体蛋白S6激酶β-1（S6K1）是一个具有吸引力的治疗靶点。在本研究中，对五种基于噻吩脲的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 ）分解分析表明，Leu97、Glu173、Val 105、Leu175、Leu97和Met225对Δ 的贡献最大。基于计算机结果，设计并合成了基于苯基吡唑的酰胺（）。生物学评价显示，表现出15.9 nM的S6K1抑制活性、中等的微粒体稳定性和理想的生物利用度。
