Department of Community Medical Technology, Faculty of Medical Technology, Mahidol University, Bangkok 10700,Thailand.
Istituto di Ricerche Farmacologiche Mario Negri IRCCS, 20156, Via Mario Negri 2, Milano,Italy.
Comb Chem High Throughput Screen. 2021;24(8):1217-1228. doi: 10.2174/1386207323666200902141907.
Sirtuin 1 (Sirt1) and sirtuin 2 (Sirt2) are NAD+-dependent histone deacetylases which play important functional roles in the removal of the acetyl group of acetyllysine substrates. Considering the dysregulation of Sirt1 and Sirt2 as etiological causes of diseases, Sirt1 and Sirt2 are lucrative target proteins for treatment, thus there has been great interest in the development of Sirt1 and Sirt2 inhibitors.
This study compiled the bioactivity data of Sirt1 and Sirt2 for the construction of quantitative structure-activity relationship (QSAR) models in accordance with the OECD principles.
Simplified molecular-input line-entry system (SMILES)-based molecular descriptors were used to characterize the molecular features of inhibitors while the Monte Carlo method of the CORAL software was employed for multivariate analysis. The dataset was subjected to 3 random splits in which each split separated the data into 4 subsets consisting of training, invisible training, calibration, and external sets.
Statistical indices for the evaluation of QSAR models suggested the good statistical quality of models of Sirt1 and Sirt2 inhibitors. Furthermore, mechanistic interpretation of molecular substructures that are responsible for modulating the bioactivity (i.e., promoters of increase or decrease of bioactivity) was extracted via the analysis of correlation weights. It exhibited molecular features involved in Sirt1 and Sirt2 inhibitors.
It is anticipated that QSAR models presented herein can be useful as guidelines in the rational design of potential Sirt1 and Sirt2 inhibitors for the treatment of Sirtuin-related diseases.
Sirtuin 1（Sirt1）和 Sirtuin 2（Sirt2）是 NAD+-依赖性组蛋白去乙酰化酶，在去除乙酰赖氨酸底物的乙酰基方面发挥着重要的功能作用。鉴于 Sirt1 和 Sirt2 的失调是疾病的病因，Sirt1 和 Sirt2 是治疗的有吸引力的靶蛋白，因此人们对 Sirt1 和 Sirt2 抑制剂的开发产生了极大的兴趣。
本研究根据 OECD 原则，编译了 Sirt1 和 Sirt2 的生物活性数据，以构建定量构效关系（QSAR）模型。
简化分子输入线输入系统（SMILES）为基础的分子描述符用于描述抑制剂的分子特征，而 CORAL 软件的蒙特卡罗方法用于多变量分析。数据集经过 3 次随机拆分，每次拆分将数据分为 4 个子集，包括训练集、看不见的训练集、校准集和外部集。
QSAR 模型评价的统计指标表明，Sirt1 和 Sirt2 抑制剂模型具有良好的统计质量。此外，通过相关权重分析提取了负责调节生物活性的分子亚结构的机制解释（即增加或降低生物活性的促进剂）。它展示了涉及 Sirt1 和 Sirt2 抑制剂的分子特征。
预计本文提出的 QSAR 模型可以作为合理设计潜在 Sirt1 和 Sirt2 抑制剂治疗 Sirtuin 相关疾病的指南。
