<i>In</i>-<i>silico</i> analysis of Sirt2 from <i>Schistosoma mansoni</i>: structures, conformations, and interactions with inhibitors

Sirtuins are NAD+-dependent lysine deacetylases member of the class III HDAC family. These are demonstrated to be therapeutic targets in parasitic diseases like schistosomiasis. Observations suggested that sirtuin enzyme is necessary for the functionality of fe/male reproductive system, due to which SmSirt2 is treated as a potential therapeutic target. There are no structural and molecular features of SmSirt2 have been reported yet. In this study, homology modeling has been used to determine the three-dimensional features of the SmSITRT2. Further, structure validation has been performed by energy minimization and Ramachandran plot. Validated structures are further subjected to molecular docking and virtual screening to find the best lead molecules for downstream analysis. Ten lead molecules were selected while comparing virtual screening of hSirt2 and SmSirt2 both. These leads are further compared with AKG2 which is known inhibitor of hSirt2 (−8.8 kcal/mol). Out of selected 10 leads, four of them (ZINC23995485 (−9.5 kcal/mol), ZINC53298162 (−9.4 kcal/mol), ZINC70927268 (−10.0 kcal/mol), ZINC89878705 (−11.2 kcal/mol)) have shown better interaction with SmSirt2, in which ZINC89878705 (−11.2 kcal/mol) shows a more compact packing as compared to AKG2 and rest of ligands. These molecules could be further subject to <i>in vitro</i> study and model of SmSirt2 has been proposed for further structure-based drug design projects concerning sirtuins from <i>Schistosoma mansoni</i>.

沉默信息调节因子（Sirtuins）是依赖烟酰胺腺嘌呤二核苷酸（NAD+）的赖氨酸去乙酰化酶，隶属于Ⅲ类组蛋白去乙酰化酶（HDAC）家族。该家族酶已被证实为血吸虫病等寄生虫疾病的治疗靶点。研究显示，sirtuin酶对雌雄生殖系统的功能行使不可或缺，因此曼氏血吸虫Sirt2（SmSirt2）被视作潜在治疗靶点。截至目前，尚未有关于SmSirt2的结构与分子特征的研究报道。本研究通过同源建模技术解析了SmSirt2的三维结构特征，随后采用能量最小化与拉马钱德兰图（Ramachandran plot）对所构建的模型进行结构验证。经验证的模型进一步用于分子对接与虚拟筛选实验，以筛选可用于后续研究的最优先导化合物。通过对比人类Sirt2（hSirt2）与SmSirt2的虚拟筛选结果，共获得10个先导化合物。将这10个先导化合物与已知的hSirt2抑制剂AKG2（结合能为-8.8 kcal/mol）进行对比分析后发现，其中4个化合物（ZINC23995485，结合能-9.5 kcal/mol；ZINC53298162，结合能-9.4 kcal/mol；ZINC70927268，结合能-10.0 kcal/mol；ZINC89878705，结合能-11.2 kcal/mol）与SmSirt2的结合效果更优；其中ZINC89878705（结合能-11.2 kcal/mol）相较于AKG2及其余配体，展现出更为紧密的结合堆积模式。上述候选化合物可进一步开展体外（in vitro）实验研究，本研究构建的SmSirt2模型可为针对曼氏血吸虫（Schistosoma mansoni）sirtuin类蛋白的结构导向药物开发项目提供参考。

搜集汇总

背景与挑战

背景概述

该数据集聚焦于曼氏血吸虫Sirt2蛋白（SmSirt2）的计算分析，通过同源建模、结构验证和虚拟筛选，研究了其三维结构、构象及与抑制剂的相互作用。研究筛选出10个先导分子，其中四个（如ZINC89878705）显示出比已知抑制剂AKG2更强的结合能力，为针对血吸虫病的Sirt2靶向药物设计提供了基础数据。数据集包含原始数据文件，适用于生物物理学、分子生物学和药物发现等领域的研究。