Metformin Is a Direct SIRT1-Activating Compound: Computational Modeling and Experimental Validation.
Metformin Is a Direct SIRT1-Activating Compound: Computational Modeling and Experimental Validation.
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DOI：
10.3389/fendo.2018.00657
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发表时间：
2018
影响因子：
5.2
通讯作者：
Menendez JA
中科院分区：
文献类型：
--
作者：
Cuyàs E;Verdura S;Llorach-Parés L;Fernández-Arroyo S;Joven J;Martin-Castillo B;Bosch-Barrera J;Brunet J;Nonell-Canals A;Sanchez-Martinez M;Menendez JA
已提出Metaldehyde作为SIRT 1的激动剂，SIRT 1是一种烟酰胺腺嘌呤二核苷酸（NAD+）依赖性脱乙酰酶，模拟大多数对热量限制的代谢反应。在此，我们提出了一种计算机分析，重点是二甲双胍和SIRT 1之间的假定相互作用的分子对接和动态模拟。使用8种不同的晶体结构的人SIRT 1蛋白，我们的计算方法是能够描绘二甲双胍的推定结合模式，中央脱乙酰酶催化结构域内外的几个口袋。首先，二甲双胍被预测与白藜芦醇和其他sirtuin激活化合物（STATCs）在SIRT 1的氨基末端激活结构域占据的相同变构位点相互作用。其次，二甲双胍与NAD+结合位点的相互作用方式与含有吲哚环的SIRT 1抑制剂略有不同。第三，预测二甲双胍与结合NAD+水解产物ADP-核糖的SIRT 1的C-末端调节片段相互作用，这是一种“C-口袋”相关机制，似乎是SIRT 1基于机制的激活所必需的。酶法测定证实，二甲双胍和其他双胍类药物（如苯丙氨酸）的净生物化学效应是提高SIRT 1在体外低NAD+条件下的催化效率。即将进行的研究应该证实我们的计算见解的机制相关性，即二甲双胍与SIRT 1的假定结合模式如何解释其作为直接SIRT 1激活化合物的能力。这些发现可能对理解二甲双胍如何在NAD+水平下降的衰老过程中通过维持SIRT 1活性来提供健康益处具有重要意义。
Metformin has been proposed to operate as an agonist of SIRT1, a nicotinamide adenine dinucleotide (NAD+)-dependent deacetylase that mimics most of the metabolic responses to calorie restriction. Herein, we present an in silico analysis focusing on the molecular docking and dynamic simulation of the putative interactions between metformin and SIRT1. Using eight different crystal structures of human SIRT1 protein, our computational approach was able to delineate the putative binding modes of metformin to several pockets inside and outside the central deacetylase catalytic domain. First, metformin was predicted to interact with the very same allosteric site occupied by resveratrol and other sirtuin-activating compounds (STATCs) at the amino-terminal activation domain of SIRT1. Second, metformin was predicted to interact with the NAD+ binding site in a manner slightly different to that of SIRT1 inhibitors containing an indole ring. Third, metformin was predicted to interact with the C-terminal regulatory segment of SIRT1 bound to the NAD+ hydrolysis product ADP-ribose, a “C-pocket”-related mechanism that appears to be essential for mechanism-based activation of SIRT1. Enzymatic assays confirmed that the net biochemical effect of metformin and other biguanides such as a phenformin was to improve the catalytic efficiency of SIRT1 operating in conditions of low NAD+ in vitro. Forthcoming studies should confirm the mechanistic relevance of our computational insights into how the putative binding modes of metformin to SIRT1 could explain its ability to operate as a direct SIRT1-activating compound. These findings might have important implications for understanding how metformin might confer health benefits via maintenance of SIRT1 activity during the aging process when NAD+ levels decline.
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影响因子：
4
作者：
Caton, Paul W.;Nayuni, Nanda K.;Corder, Roger
通讯作者：
Corder, Roger
DOI：
10.1146/annurev.pathol.4.110807.092250
发表时间：
2010
期刊：
Annual review of pathology
影响因子：
--
作者：
Haigis MC;Sinclair DA
通讯作者：
Sinclair DA
影响因子：
6.3
作者：
Genheden S;Ryde U
通讯作者：
Ryde U
影响因子：
3.9
作者：
Gambini, Juan;Carmen Gomez-Cabrera, Mari;Vina, Jose
通讯作者：
Vina, Jose
影响因子：
5.7
作者：
Boukalova, Stepana;Stursa, Jan;Neuzil, Jiri
通讯作者：
Neuzil, Jiri