Discovery of dual-target natural inhibitors of meprins α and β metalloproteases for inflammation regulation: pharmacophore modelling, molecular docking, ADME prediction, and molecular dynamics studies.

IF 2.3 3区 环境科学与生态学 Q3 CHEMISTRY, MULTIDISCIPLINARY
L Eltaib, A A Alzain
{"title":"Discovery of dual-target natural inhibitors of meprins α and β metalloproteases for inflammation regulation: pharmacophore modelling, molecular docking, ADME prediction, and molecular dynamics studies.","authors":"L Eltaib, A A Alzain","doi":"10.1080/1062936X.2023.2277425","DOIUrl":null,"url":null,"abstract":"<p><p>Meprins, zinc-dependent metalloproteinases belonging to the metzincin family, have been associated with various inflammatory diseases due to their abnormal expression and activity. In this study, we utilized pharmacophore modelling to identify crucial features for discovering potential dual inhibitors targeting meprins α and β. We screened four pharmacophoric features against a library of 270,540 natural compounds from the Zinc database, resulting in 84,092 matching compounds. Molecular docking was then performed on these compounds, targeting the active sites of meprins α and β. Docking results revealed six compounds capable of interacting with both isoforms, with binding affinities ranging from -10.0 to -10.5 kcal/mol and -6.9 to -9.9 kcal/mol for meprin α and β, respectively. Among these compounds, ZINC000008790788 and ZINC000095099469 displayed superior docking scores and MM-GBSA binding free energy compared to reference ligands. Furthermore, these two compounds exhibited acceptable predicted pharmacokinetic properties and stable interactions with meprins α and β during molecular dynamics simulations. This study presents a comprehensive approach for identifying potential dual inhibitors of meprin α and β, offering insights into the development of therapeutic interventions for inflammatory diseases associated with meprin dysregulation.</p>","PeriodicalId":21446,"journal":{"name":"SAR and QSAR in Environmental Research","volume":" ","pages":"1-23"},"PeriodicalIF":2.3000,"publicationDate":"2023-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"SAR and QSAR in Environmental Research","FirstCategoryId":"93","ListUrlMain":"https://doi.org/10.1080/1062936X.2023.2277425","RegionNum":3,"RegionCategory":"环境科学与生态学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q3","JCRName":"CHEMISTRY, MULTIDISCIPLINARY","Score":null,"Total":0}
引用次数: 0

Abstract

Meprins, zinc-dependent metalloproteinases belonging to the metzincin family, have been associated with various inflammatory diseases due to their abnormal expression and activity. In this study, we utilized pharmacophore modelling to identify crucial features for discovering potential dual inhibitors targeting meprins α and β. We screened four pharmacophoric features against a library of 270,540 natural compounds from the Zinc database, resulting in 84,092 matching compounds. Molecular docking was then performed on these compounds, targeting the active sites of meprins α and β. Docking results revealed six compounds capable of interacting with both isoforms, with binding affinities ranging from -10.0 to -10.5 kcal/mol and -6.9 to -9.9 kcal/mol for meprin α and β, respectively. Among these compounds, ZINC000008790788 and ZINC000095099469 displayed superior docking scores and MM-GBSA binding free energy compared to reference ligands. Furthermore, these two compounds exhibited acceptable predicted pharmacokinetic properties and stable interactions with meprins α and β during molecular dynamics simulations. This study presents a comprehensive approach for identifying potential dual inhibitors of meprin α and β, offering insights into the development of therapeutic interventions for inflammatory diseases associated with meprin dysregulation.

meprins α和β金属蛋白酶炎症调节双靶点天然抑制剂的发现:药效团建模、分子对接、ADME预测和分子动力学研究。
Meprins是锌依赖性金属蛋白酶,属于锌依赖性金属蛋白酶家族,由于其异常表达和活性与多种炎症性疾病有关。在这项研究中,我们利用药效团模型来确定发现潜在的针对meprins α和β的双重抑制剂的关键特征。我们从锌数据库的270,540个天然化合物库中筛选了四个药效特征,得到84,092个匹配的化合物。然后对这些化合物进行分子对接,靶向meprins α和β的活性位点。对接结果显示,6个化合物能够与两种同工异构体相互作用,对meprin α和β的结合亲和力分别在-10.0 ~ -10.5 kcal/mol和-6.9 ~ -9.9 kcal/mol之间。其中,ZINC000008790788和ZINC000095099469的对接分数和MM-GBSA结合自由能均优于参考配体。此外,在分子动力学模拟中,这两种化合物表现出可接受的预测药代动力学性质,并与meprins α和β稳定相互作用。本研究提出了一种全面的方法来识别meprin α和β的潜在双重抑制剂,为与meprin失调相关的炎症性疾病的治疗干预的发展提供了见解。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
求助全文
约1分钟内获得全文 求助全文
来源期刊
CiteScore
5.20
自引率
20.00%
发文量
78
审稿时长
>24 weeks
期刊介绍: SAR and QSAR in Environmental Research is an international journal welcoming papers on the fundamental and practical aspects of the structure-activity and structure-property relationships in the fields of environmental science, agrochemistry, toxicology, pharmacology and applied chemistry. A unique aspect of the journal is the focus on emerging techniques for the building of SAR and QSAR models in these widely varying fields. The scope of the journal includes, but is not limited to, the topics of topological and physicochemical descriptors, mathematical, statistical and graphical methods for data analysis, computer methods and programs, original applications and comparative studies. In addition to primary scientific papers, the journal contains reviews of books and software and news of conferences. Special issues on topics of current and widespread interest to the SAR and QSAR community will be published from time to time.
×
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