In silico drug discovery of SIRT2 inhibitors from natural source as anticancer agents.
In silico drug discovery of SIRT2 inhibitors from natural source as anticancer agents.
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DOI：
10.1038/s41598-023-28226-7
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发表时间：
2023-02-07
影响因子：
4.6
通讯作者：
中科院分区：
文献类型：
--
作者：
Sirtuin 2 （SIRT2）是Sirtuin蛋白家族的一员，该家族包括依赖NAD+的赖氨酸去乙酰化酶，并组织多种生物过程。不同形式的癌症与SIRT2活性失调有关。因此，鉴定SIRT2的有效抑制剂在药物发现界引起了相当大的关注。在目前的研究中，利用硅技术挖掘天然产物图谱（NPAtlas）数据库来寻找潜在的SIRT2抑制剂。首先，根据可获得的实验数据评估所采用的对接协议预测配体- sirt2结合模式的性能。根据预测的对接分数，选择最有希望的NPAtlas分子进行分子动力学模拟，然后计算结合能。基于MM-GBSA在200 ns MD过程中的结合能估计，鉴定出NPA009578、NPA006805和NPA001884三个NPAtlas化合物对SIRT2蛋白的ΔGbinding作用优于天然配体（SirReal2），其值分别为- 59.9、- 57.4、- 53.5和- 49.7 kcal/mol。根据结构和能量评价，鉴定的NPAtlas化合物在200 ns MD过程中是稳定的。预测了鉴定的NPAtlas分子的药物相似性和药代动力学特性，并预测了其强大的生物利用度。总之，目前的结果表明SIRT2的有效抑制剂值得更多的体外/体内研究。
Sirtuin 2 (SIRT2) is a member of the sirtuin protein family, which includes lysine deacylases that are NAD+-dependent and organize several biological processes. Different forms of cancer have been associated with dysregulation of SIRT2 activity. Hence, identifying potent inhibitors for SIRT2 has piqued considerable attention in the drug discovery community. In the current study, the Natural Products Atlas (NPAtlas) database was mined to hunt potential SIRT2 inhibitors utilizing in silico techniques. Initially, the performance of the employed docking protocol to anticipate ligand-SIRT2 binding mode was assessed according to the accessible experimental data. Based on the predicted docking scores, the most promising NPAtlas molecules were selected and submitted to molecular dynamics (MD) simulations, followed by binding energy computations. Based on the MM-GBSA binding energy estimations over a 200 ns MD course, three NPAtlas compounds, namely NPA009578, NPA006805, and NPA001884, were identified with better ΔGbinding towards SIRT2 protein than the native ligand (SirReal2) with values of − 59.9, − 57.4, − 53.5, and − 49.7 kcal/mol, respectively. On the basis of structural and energetic assessments, the identified NPAtlas compounds were confirmed to be steady over a 200 ns MD course. The drug-likeness and pharmacokinetic characteristics of the identified NPAtlas molecules were anticipated, and robust bioavailability was predicted. Conclusively, the current results propose potent inhibitors for SIRT2 deserving more in vitro/in vivo investigation.
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影响因子：
4.8
作者：
Hoffmann, Gesine;Breitenbuecher, Frank;Ehrenhofer-Murray, Ann E.
通讯作者：
Ehrenhofer-Murray, Ann E.
影响因子：
5.6
作者：
de Oliveira RM;Sarkander J;Kazantsev AG;Outeiro TF
通讯作者：
Outeiro TF
影响因子：
8.6
作者：
Heller SR;McNaught A;Pletnev I;Stein S;Tchekhovskoi D
通讯作者：
Tchekhovskoi D
影响因子：
3.9
作者：
Behari J
通讯作者：
Behari J
影响因子：
16
作者：
Avalos, JL;Celic, I;Wolberger, C
通讯作者：
Wolberger, C