Faculty of Pharmacy, Universitas Indonesia, Depok, West Java, 16424, Indonesia; Faculty of Pharmacy, Universitas Surabaya, Surabaya, East Java, 60284, Indonesia.
Faculty of Medicine, Universitas Indonesia, Salemba, Jakarta, 10430, Indonesia.
Comput Biol Chem. 2019 Dec;83:107096. doi: 10.1016/j.compbiolchem.2019.107096. Epub 2019 Jul 18.
Sirtuin 1 (SIRT1) is a class III family of protein histone deacetylases involved in NAD-dependent deacetylation reactions. It has been suggested that SIRT1 activators may have a protective role against type 2 diabetes, the aging process, and inflammation. This study aimed to explore and identify medicinal plant compounds from Indonesian Herbal Database (HerbalDB) that might potentially become a candidate for SIRT1 activators through a combination of in silico and in vitro methods. Two pharmacophore models were developed using co-crystalized ligands that allosterically bind with SIRT1 similar to the putative ligands used by SIRT1 activators. Then, these were used for the virtual screening of HerbalDB. The identified compounds were subjected to molecular docking and 50 ns molecular dynamics simulation. Molecular dynamics simulation was analyzed using MM-GB(PB)SA methods. The compounds identified by these methods were tested in an in vitro study using a SIRT-Glo™ luminescence assay. Virtual screening using structure-based pharmacophores predicted that mulberrin as the best candidate SIRT1 activator. Virtual screening using ligand-based pharmacophores predicted that gartanin, quinidine, and quinine to be the best candidates as SIRT1 activators. The molecular docking studies showed the important residues involved were Ile223 and Ile227 at the allosteric region. The MM-GB(PB)SA calculations confirmed that mulberrin, gartanin, quinidine, quinine showed activity at allosteric region and their EC in vitro values are 2.10; 1.79; 1.71; 1.14 μM, respectively. Based on in silico and in vitro study results, mulberin, gartanin, quinidine, and quinine had good activity as SIRT1 activators.
Sirtuin 1（SIRT1）是一种参与 NAD 依赖性去乙酰化反应的 III 类蛋白组蛋白去乙酰酶。有人提出，SIRT1 激活剂可能对 2 型糖尿病、衰老过程和炎症具有保护作用。本研究旨在通过计算机模拟和体外方法相结合，从印度尼西亚草药数据库（HerbalDB）中探索和鉴定可能成为 SIRT1 激活剂候选药物的药用植物化合物。使用与 SIRT1 变构结合的共结晶配体开发了两种药效团模型，这些配体类似于 SIRT1 激活剂使用的假定配体。然后，将这些模型用于 HerbalDB 的虚拟筛选。鉴定出的化合物进行分子对接和 50ns 分子动力学模拟。使用 MM-GB(PB)SA 方法分析分子动力学模拟。使用 SIRT-Glo™ 发光测定法在体外研究中测试了这些方法鉴定出的化合物。基于结构的药效团虚拟筛选预测，mulberrin 是最好的 SIRT1 激活剂候选物。基于配体的药效团虚拟筛选预测，gartanin、quinidine 和 quinine 是最好的 SIRT1 激活剂候选物。分子对接研究表明，变构区域涉及重要残基为 Ile223 和 Ile227。MM-GB(PB)SA 计算证实，mulberrin、gartanin、quinidine 和 quinine 在变构区域均具有活性，其体外 EC 值分别为 2.10、1.79、1.71 和 1.14 μM。基于计算机模拟和体外研究结果，mulberin、gartanin、quinidine 和 quinine 具有良好的 SIRT1 激活活性。
