Aim: The aim of the study was to develop new SIRT1 activator compounds, for this aim, we used virtual screening and molecular dynamics methods, which have been important tools for new hit compound searches.

Background: Recently, with the progress of computing technology, it has been possible to obtain higher efficiency and lower costs for drug discovery. With in silico research and drug design, there is a reduction in time-consuming and expensive experimental work. An NAD+ dependent histone deacetylase enzyme, Sirtuin 1 (SIRT1), is involved in a variety of human disorders such as type II diabetes, cancer, obesity, and aging. Activation of SIRT1 could be useful for longevity and treating metabolic disorders.

Objective: We used computational methods to develop new SIRT1 activator compounds.

Methods: Firstly, virtual screening studies on the human SIRT1 enzyme were carried out. We used approximately 150.000 commercially available compounds from the Zinc database, which include FDA-approved drugs. According to virtual screening results, we selected seven potent activators. Then we compared these hit compounds with known activators by using docking methods. One of these hit compounds, acebutolol, is an FDA-approved drug, and was selected for additional studies using molecular dynamics simulations.

Results: Seven hit compounds were identified with database screening. Each showed strong interactions with SIRT1, and acebutolol formed H-bonds with the important active site residues, Asn226 and/or Glu230 during the dynamics simulation.

Conclusion: Based on our in silico studies, the seven most promising compounds, especially acebutolol, showed promising SIRT1 activator potency. The results may be used to design new selective and more potent SIRT1 activator drugs.

目的：该研究的目的是开发新的 SIRT1 激活剂化合物，为此，我们使用了虚拟筛选和分子动力学方法，这些方法已成为新命中化合物搜索的重要工具。

背景：近年来，随着计算技术的进步，新药研发的效率更高、成本更低。通过计算机研究和药物设计，可以减少耗时且昂贵的实验工作。NAD+ 依赖性组蛋白去乙酰化酶 Sirtuin 1 (SIRT1) 与多种人类疾病有关，例如 II 型糖尿病、癌症、肥胖症和衰老。SIRT1 的激活可能有助于长寿和治疗代谢紊乱。

目标：我们使用计算方法开发新的 SIRT1 激活剂化合物。

方法：首先，对人SIRT1酶进行虚拟筛选研究。我们使用了来自 Zinc 数据库的大约 150.000 种市售化合物，其中包括 FDA 批准的药物。根据虚拟筛选结果，我们选择了七种有效的激活剂。然后我们通过对接方法将这些命中化合物与已知的激活剂进行了比较。其中一种热门化合物醋丁洛尔是 FDA 批准的药物，并被选中用于使用分子动力学模拟的其他研究。

结果：通过数据库筛选鉴定了七种命中化合物。每个都显示出与 SIRT1 的强相互作用，并且在动力学模拟过程中，醋丁洛尔与重要的活性位点残基 Asn226 和/或 Glu230 形成 H 键。

结论：根据我们的计算机模拟研究，七种最有希望的化合物，尤其是醋丁洛尔，显示出有希望的 SIRT1 激活剂效力。结果可用于设计新的选择性和更有效的 SIRT1 激活剂药物。