抗菌肽与肾毒性作用靶点之间的相互作用:分子动力学模拟。

IF 1.1 Q4 PHARMACOLOGY & PHARMACY
Yury Lisnyak, Artur Martynov, Boris Farber
{"title":"抗菌肽与肾毒性作用靶点之间的相互作用:分子动力学模拟。","authors":"Yury Lisnyak, Artur Martynov, Boris Farber","doi":"10.2174/1574886318666230905100924","DOIUrl":null,"url":null,"abstract":"<p><strong>Objectives: </strong>Polymyxin is the last line of defense against resistant forms of microorganisms, but it has significant nephrotoxicity. One of the directions in reducing the nephrotoxicity of polymyxin is to modify the charge of the molecule and accordingly, to change the topicity of the polymyxin derivative to the renal megalin. Such modification can lead to a decrease in the accumulation of polymyxin in the kidneys and reduce its toxicity while maintaining its antimicrobial properties. The study aimed to investigate the structural aspects of polymyxin nephrotoxicity at the atomic level to promote the more purposeful development of the polymyxin's derivatives with the lower nephrotoxic action.</p><p><strong>Materials and methods: </strong>The molecular dynamics simulations of the complexes of polymyxin B and its derivative NAB7061 (that carries only three positive charges located within the macrocycle) with megalin were performed in program package YASARA structure with explicit water (TIP3P) and ions (0.9 % NaCl) in NPT ensemble using the AMRER03 force field. After 10 ns equilibration, each system was simulated at 298 K and pH 7.4 for a 25 ns production phase. Simulations were run twice for each molecular system.</p><p><strong>Results: </strong>By molecular dynamics simulations, the possibility was shown for polymyxin to form a stable complex with two neighbor structural domains of megalin in accord with the universal mechanism of binding the cationic ligands by ligand-binding CR repeats of the LDLR-family receptors. It was reported that interactions of megalin with polymyxin were stronger than with its derivative having no positively charged groups outside the macrocycle. The structural prerequisites of these differences were revealed, explaining the less nephrotoxicity of such derivatives compared to polymyxin.</p><p><strong>Conclusion: </strong>Comparative molecular dynamics simulations of megalin interactions with polymyxin B and its derivative NAB7061, which carries no positive charges outside the macrocycle, revealed the possible structural prerequisites for the lower nephrotoxic action of such polymyxin derivatives. The weakening of polymyxins binding with megalin may become an effective preventive measure against polymyxin-induced nephrotoxicity.</p>","PeriodicalId":10777,"journal":{"name":"Current drug safety","volume":null,"pages":null},"PeriodicalIF":1.1000,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Interactions Between Antimicrobial Peptides and Targets Responsible for their Nephrotoxic Action: Molecular Dynamics Simulations.\",\"authors\":\"Yury Lisnyak, Artur Martynov, Boris Farber\",\"doi\":\"10.2174/1574886318666230905100924\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Objectives: </strong>Polymyxin is the last line of defense against resistant forms of microorganisms, but it has significant nephrotoxicity. One of the directions in reducing the nephrotoxicity of polymyxin is to modify the charge of the molecule and accordingly, to change the topicity of the polymyxin derivative to the renal megalin. Such modification can lead to a decrease in the accumulation of polymyxin in the kidneys and reduce its toxicity while maintaining its antimicrobial properties. The study aimed to investigate the structural aspects of polymyxin nephrotoxicity at the atomic level to promote the more purposeful development of the polymyxin's derivatives with the lower nephrotoxic action.</p><p><strong>Materials and methods: </strong>The molecular dynamics simulations of the complexes of polymyxin B and its derivative NAB7061 (that carries only three positive charges located within the macrocycle) with megalin were performed in program package YASARA structure with explicit water (TIP3P) and ions (0.9 % NaCl) in NPT ensemble using the AMRER03 force field. After 10 ns equilibration, each system was simulated at 298 K and pH 7.4 for a 25 ns production phase. Simulations were run twice for each molecular system.</p><p><strong>Results: </strong>By molecular dynamics simulations, the possibility was shown for polymyxin to form a stable complex with two neighbor structural domains of megalin in accord with the universal mechanism of binding the cationic ligands by ligand-binding CR repeats of the LDLR-family receptors. It was reported that interactions of megalin with polymyxin were stronger than with its derivative having no positively charged groups outside the macrocycle. The structural prerequisites of these differences were revealed, explaining the less nephrotoxicity of such derivatives compared to polymyxin.</p><p><strong>Conclusion: </strong>Comparative molecular dynamics simulations of megalin interactions with polymyxin B and its derivative NAB7061, which carries no positive charges outside the macrocycle, revealed the possible structural prerequisites for the lower nephrotoxic action of such polymyxin derivatives. The weakening of polymyxins binding with megalin may become an effective preventive measure against polymyxin-induced nephrotoxicity.</p>\",\"PeriodicalId\":10777,\"journal\":{\"name\":\"Current drug safety\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":1.1000,\"publicationDate\":\"2024-01-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Current drug safety\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://doi.org/10.2174/1574886318666230905100924\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q4\",\"JCRName\":\"PHARMACOLOGY & PHARMACY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Current drug safety","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.2174/1574886318666230905100924","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q4","JCRName":"PHARMACOLOGY & PHARMACY","Score":null,"Total":0}
引用次数: 0

摘要

目的:多粘菌素是抵抗耐药性微生物的最后一道防线,但它具有明显的肾毒性。降低多粘菌素肾毒性的方向之一是改变分子的电荷,从而改变多粘菌素衍生物对肾脏巨球蛋白的主题性。这种改变可以减少多粘菌素在肾脏中的蓄积,降低其毒性,同时保持其抗菌特性。该研究旨在从原子水平研究多粘菌素肾毒性的结构方面,以促进更有针对性地开发具有较低肾毒性作用的多粘菌素衍生物:多粘菌素 B 及其衍生物 NAB7061(在大循环中只带三个正电荷)与巨霉素的复合物的分子动力学模拟是在程序包 YASARA 结构中进行的,其中包含显式水(TIP3P)和离子(0.9 % NaCl),并在 NPT 集合中使用 AMRER03 力场。经过 10 ns 的平衡后,每个系统在 298 K 和 pH 7.4 的条件下模拟了 25 ns 的生产阶段。每个分子体系模拟两次:通过分子动力学模拟,多粘菌素有可能与 megalin 的两个相邻结构域形成稳定的复合物,这与 LDLR 家族受体的配体结合 CR 重复序列结合阳离子配体的普遍机制一致。据报道,巨球蛋白与多粘菌素的相互作用强于与其大环外不带正电荷基团的衍生物的相互作用。研究揭示了这些差异的结构前提,从而解释了为什么与多粘菌素相比,这种衍生物的肾毒性较低:结论:通过对巨球蛋白与多粘菌素 B 及其衍生物 NAB7061(其大循环外不带有正电荷)相互作用的分子动力学比较模拟,发现了此类多粘菌素衍生物具有较低肾毒性作用的可能结构前提。减弱多粘菌素与巨球蛋白的结合可能成为预防多粘菌素引起的肾毒性的有效措施。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Interactions Between Antimicrobial Peptides and Targets Responsible for their Nephrotoxic Action: Molecular Dynamics Simulations.

Objectives: Polymyxin is the last line of defense against resistant forms of microorganisms, but it has significant nephrotoxicity. One of the directions in reducing the nephrotoxicity of polymyxin is to modify the charge of the molecule and accordingly, to change the topicity of the polymyxin derivative to the renal megalin. Such modification can lead to a decrease in the accumulation of polymyxin in the kidneys and reduce its toxicity while maintaining its antimicrobial properties. The study aimed to investigate the structural aspects of polymyxin nephrotoxicity at the atomic level to promote the more purposeful development of the polymyxin's derivatives with the lower nephrotoxic action.

Materials and methods: The molecular dynamics simulations of the complexes of polymyxin B and its derivative NAB7061 (that carries only three positive charges located within the macrocycle) with megalin were performed in program package YASARA structure with explicit water (TIP3P) and ions (0.9 % NaCl) in NPT ensemble using the AMRER03 force field. After 10 ns equilibration, each system was simulated at 298 K and pH 7.4 for a 25 ns production phase. Simulations were run twice for each molecular system.

Results: By molecular dynamics simulations, the possibility was shown for polymyxin to form a stable complex with two neighbor structural domains of megalin in accord with the universal mechanism of binding the cationic ligands by ligand-binding CR repeats of the LDLR-family receptors. It was reported that interactions of megalin with polymyxin were stronger than with its derivative having no positively charged groups outside the macrocycle. The structural prerequisites of these differences were revealed, explaining the less nephrotoxicity of such derivatives compared to polymyxin.

Conclusion: Comparative molecular dynamics simulations of megalin interactions with polymyxin B and its derivative NAB7061, which carries no positive charges outside the macrocycle, revealed the possible structural prerequisites for the lower nephrotoxic action of such polymyxin derivatives. The weakening of polymyxins binding with megalin may become an effective preventive measure against polymyxin-induced nephrotoxicity.

求助全文
通过发布文献求助,成功后即可免费获取论文全文。 去求助
来源期刊
Current drug safety
Current drug safety PHARMACOLOGY & PHARMACY-
CiteScore
2.10
自引率
0.00%
发文量
112
期刊介绍: Current Drug Safety publishes frontier articles on all the latest advances on drug safety. The journal aims to publish the highest quality research articles, reviews and case reports in the field. Topics covered include: adverse effects of individual drugs and drug classes, management of adverse effects, pharmacovigilance and pharmacoepidemiology of new and existing drugs, post-marketing surveillance. The journal is essential reading for all researchers and clinicians involved in drug safety.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术官方微信