三聚氰胺结构类似物与钙传感受体相互作用的硅学分析:潜在的肾毒性

IF 3.1 Q2 TOXICOLOGY Computational Toxicology Pub Date : 2024-10-15 DOI:10.1016/j.comtox.2024.100333
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引用次数: 0

摘要

近年来,三聚氰胺及其结构类似物作为包括蛋白质补充剂在内的各种食品的掺假物,其肾毒性作用已被广泛研究。以往的研究已经证明,某些小分子物质可以改变钙传感受体(CaSR)的功能,从而导致肾毒性。例如,在体外环境中已观察到三聚氰胺与 CaSR 的异构结合位点相互作用,导致 CaSR 激活失控。这种激活会产生活性氧,最终导致肾细胞凋亡和/或坏死。本研究利用硅学分子模型评估了蛋白质补充剂中四种常见掺杂物(三聚氰胺、三聚氰酸、尿酸和三聚氰胺氰尿酸盐)的 CaSR 结合情况。利用薛定谔的 Maestro 对接软件(13.2.128 版),该对接研究将非共价超精密模式与分子力学-广义生比表面积(MM-GBSA)模拟相结合,以提高结合亲和力预测的准确性。这项研究发现,三聚氰酸、尿酸和三聚氰胺氰尿酸盐比三聚氰胺具有更高的 CaSR 结合亲和力。有趣的是,三聚氰胺氰尿酸盐与 CaSR 的结合潜力最高。先前的动物研究报告称,大鼠肾脏在服用三聚氰胺后会出现高浓度的三聚氰胺氰尿酸盐复合物。这些发现从分子上解释了三聚氰胺氰尿酸盐复合物诱发的肾毒性。这项研究为三聚氰胺及其类似物和复合物可能导致肾毒性的机制提供了新的见解。
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In silico analysis of the melamine structural analogues interaction with calcium-sensing receptor: A potential for nephrotoxicity
In recent years, melamine, and its structural analogues, as adulterants in various food products including protein supplements, have been widely studied for their nephrotoxic effects. Previous research has presented evidence that certain small molecules can alter the calcium-sensing receptor (CaSR) function, contributing to nephrotoxicity. Melamine, for example, has been observed in in vitro settings to interact with the allosteric binding site of CaSR, resulting in uncontrolled CaSR activation. This activation results in the production of reactive oxygen species, which eventually causes kidney cell apoptosis and/or necrosis. The present research used the in silico molecular modelling to evaluate the CaSR binding profiles of four common adulterants in protein supplements: melamine, cyanuric acid, uric acid, and melamine cyanurate. Using Schrödinger’s Maestro docking software (version 13.2.128), the docking studies coupled a noncovalent extra precision mode with the molecular mechanics-generalized born surface area (MM-GBSA) simulation for enhanced binding affinity prediction accuracy. This study identified that cyanuric acid, uric acid, and melamine cyanurate have greater CaSR binding affinities than melamine. Interestingly, melamine cyanurate had the highest binding potential to CaSR. Previous animal studies have reported high concentrations of melamine cyanurate complex in rat kidneys following melamine administration. These findings demonstrate a molecular explanation melamine cyanurate complex-induced nephrotoxicity. This research offers new insight regarding the probable mechanism through which melamine, its analogues, and complexes may cause nephrotoxicity.
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来源期刊
Computational Toxicology
Computational Toxicology Computer Science-Computer Science Applications
CiteScore
5.50
自引率
0.00%
发文量
53
审稿时长
56 days
期刊介绍: Computational Toxicology is an international journal publishing computational approaches that assist in the toxicological evaluation of new and existing chemical substances assisting in their safety assessment. -All effects relating to human health and environmental toxicity and fate -Prediction of toxicity, metabolism, fate and physico-chemical properties -The development of models from read-across, (Q)SARs, PBPK, QIVIVE, Multi-Scale Models -Big Data in toxicology: integration, management, analysis -Implementation of models through AOPs, IATA, TTC -Regulatory acceptance of models: evaluation, verification and validation -From metals, to small organic molecules to nanoparticles -Pharmaceuticals, pesticides, foods, cosmetics, fine chemicals -Bringing together the views of industry, regulators, academia, NGOs
期刊最新文献
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