核糖体蛋白S6激酶β-1（S6K1）被认为是治疗肥胖症、2型糖尿病和癌症等多种疾病的潜在靶点。开发新型的S6K1抑制剂是药物化学家们的紧急和重要任务。本研究应用一种有效的集合虚拟筛选方法，包括共通特征药效团模型、3D-QSAR药效团模型、朴素贝叶斯分类器模型和分子对接，从Biodeiversity数据库的29,158个化合物中发现了潜在的S6K1抑制剂。最终，7个命中物表现出可观的特性，被认为是抗S6K1的潜在抑制剂。此外，仔细分析这7个命中物与S6K1活性位点的关键残基之间的相互作用，并将其与参考化合物PF-4708671进行比较，发现有2个命中物呈现出更好的结合模式。为了进一步研究这两个命中物与在模拟生理条件下的S6K1之间的相互作用机制，进行了分子动力学模拟。S6K1-Hit1和S6K1-Hit2的ΔGbind能量分别为-111.47±1.29和-54.29±1.19 kJ/mol。此外，对这些结果的深层次分析表明，Hit1是最稳定的复合物，它可以稳定地结合到S6K1活性位点，与所有关键残基相互作用，并诱导H1、H2和M环区域的改变。因此，鉴定出的Hit1可能是开发新型S6K1抑制剂治疗各种代谢性疾病的有前途的先导化合物。©2023年作者，由Springer-Verlag GmbH Germany 的独家许可，属于Springer Nature的一部分。

Ribosomal protein S6 kinase beta-1 (S6K1) is considered a potential target for the treatment of various diseases, such as obesity, type II diabetes, and cancer. Development of novel S6K1 inhibitors is an urgent and important task for the medicinal chemists. In this research, an effective ensemble-based virtual screening method, including common feature pharmacophore model, 3D-QSAR pharmacophore model, naïve Bayes classifier model, and molecular docking, was applied to discover potential S6K1 inhibitors from BioDiversity database with 29,158 compounds. Finally, 7 hits displayed considerable properties and considered as potential inhibitors against S6K1. Further, carefully analyzing the interactions between these 7 hits and key residues in the S6K1 active site, and comparing them with the reference compound PF-4708671, it was found that 2 hits exhibited better binding patterns. In order to further investigate the mechanism of the interactions between 2 hits and S6K1 at simulated physiological conditions, the molecular dynamics simulation was performed. The ΔGbind energies for S6K1-Hit1 and S6K1-Hit2 were - 111.47 ± 1.29 and - 54.29 ± 1.19 kJ mol-1, respectively. Furthermore, deep analysis of these results revealed that Hit1 was the most stable complex, which can stably bind to S6K1 active site, interact with all of the key residues, and induce H1, H2, and M-loop regions changes. Therefore, the identified Hit1 may be a promising lead compound for developing new S6K1 inhibitor for various metabolic diseases treatment.© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.