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二甲双胍是一种直接激活SIRT1的化合物:计算建模与实验验证。

Metformin Is a Direct SIRT1-Activating Compound: Computational Modeling and Experimental Validation.

作者信息

Cuyàs Elisabet, Verdura Sara, Llorach-Parés Laura, Fernández-Arroyo Salvador, Joven Jorge, Martin-Castillo Begoña, Bosch-Barrera Joaquim, Brunet Joan, Nonell-Canals Alfons, Sanchez-Martinez Melchor, Menendez Javier A

机构信息

ProCURE (Program Against Cancer Therapeutic Resistance), Metabolism and Cancer Group, Catalan Institute of Oncology, Girona, Spain.

Girona Biomedical Research Institute (IDIBGI), Girona, Spain.

出版信息

Front Endocrinol (Lausanne). 2018 Nov 6;9:657. doi: 10.3389/fendo.2018.00657. eCollection 2018.

Abstract

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 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 . 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 maintenance of SIRT1 activity during the aging process when NAD levels decline.

摘要

二甲双胍被认为可作为SIRT1的激动剂发挥作用,SIRT1是一种烟酰胺腺嘌呤二核苷酸(NAD)依赖性脱乙酰酶,可模拟大部分对热量限制的代谢反应。在此,我们进行了一项分析,重点关注二甲双胍与SIRT1之间假定相互作用的分子对接和动态模拟。利用人类SIRT1蛋白的八种不同晶体结构,我们的计算方法能够描绘出二甲双胍与中央脱乙酰酶催化结构域内外几个口袋的假定结合模式。首先,预测二甲双胍会与白藜芦醇和其他沉默调节蛋白激活化合物(STATCs)在SIRT1氨基末端激活结构域所占据的同一别构位点相互作用。其次,预测二甲双胍与NAD结合位点的相互作用方式与含有吲哚环的SIRT1抑制剂略有不同。第三,预测二甲双胍会与结合NAD水解产物ADP - 核糖的SIRT1的C末端调节片段相互作用,这是一种与“C口袋”相关的机制,似乎对基于机制的SIRT1激活至关重要。酶促试验证实,二甲双胍和其他双胍类药物(如苯乙双胍)的净生化作用是提高在低NAD条件下运行的SIRT1的催化效率。即将开展的研究应证实我们关于二甲双胍与SIRT1假定结合模式如何解释其作为直接SIRT1激活化合物能力的计算见解的机制相关性。这些发现可能对理解二甲双胍如何在衰老过程中NAD水平下降时通过维持SIRT1活性来赋予健康益处具有重要意义。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/249b/6232372/8950c7f4561d/fendo-09-00657-g0001.jpg

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