Martina Hrast Rambaher, Irena Zdovc, Nina Kočevar Glavač, Stanislav Gobec, Rok Frlan
{"title":"Mur连接酶F作为黄酮类化合物槲皮素、杨梅素和(-)-表儿茶素的新靶点。","authors":"Martina Hrast Rambaher, Irena Zdovc, Nina Kočevar Glavač, Stanislav Gobec, Rok Frlan","doi":"10.1007/s10822-023-00535-z","DOIUrl":null,"url":null,"abstract":"<div><p>MurC, D, E, and F are ATP-dependent ligases involved in the stepwise assembly of the tetrapeptide stem of forming peptidoglycan. As highly conserved targets found exclusively in bacterial cells, they are of significant interest for antibacterial drug discovery. In this study, we employed a computer-aided molecular design approach to identify potential inhibitors of MurF. A biochemical inhibition assay was conducted, screening twenty-four flavonoids and related compounds against MurC-F, resulting in the identification of quercitrin, myricetin, and (–)-epicatechin as MurF inhibitors with IC<sub>50</sub> values of 143 µM, 139 µM, and 92 µM, respectively. Notably, (–)-epicatechin demonstrated mixed type inhibition with ATP and uncompetitive inhibition with <span>d</span>-Ala-<span>d</span>-Ala dipeptide and UM3DAP substrates. Furthermore, <i>in silico</i> analysis using Sitemap and subsequent docking analysis using Glide revealed two plausible binding sites for (–)-epicatechin. The study also investigated the crucial structural features required for activity, with a particular focus on the substitution pattern and hydroxyl group positions, which were found to be important for the activity. The study highlights the significance of computational approaches in targeting essential enzymes involved in bacterial peptidoglycan synthesis.</p><h3>Graphical abstract</h3>\n <div><figure><div><div><picture><source><img></source></picture></div></div></figure></div>\n </div>","PeriodicalId":621,"journal":{"name":"Journal of Computer-Aided Molecular Design","volume":"37 12","pages":"721 - 733"},"PeriodicalIF":3.0000,"publicationDate":"2023-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Mur ligase F as a new target for the flavonoids quercitrin, myricetin, and (–)-epicatechin\",\"authors\":\"Martina Hrast Rambaher, Irena Zdovc, Nina Kočevar Glavač, Stanislav Gobec, Rok Frlan\",\"doi\":\"10.1007/s10822-023-00535-z\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><p>MurC, D, E, and F are ATP-dependent ligases involved in the stepwise assembly of the tetrapeptide stem of forming peptidoglycan. As highly conserved targets found exclusively in bacterial cells, they are of significant interest for antibacterial drug discovery. In this study, we employed a computer-aided molecular design approach to identify potential inhibitors of MurF. A biochemical inhibition assay was conducted, screening twenty-four flavonoids and related compounds against MurC-F, resulting in the identification of quercitrin, myricetin, and (–)-epicatechin as MurF inhibitors with IC<sub>50</sub> values of 143 µM, 139 µM, and 92 µM, respectively. Notably, (–)-epicatechin demonstrated mixed type inhibition with ATP and uncompetitive inhibition with <span>d</span>-Ala-<span>d</span>-Ala dipeptide and UM3DAP substrates. Furthermore, <i>in silico</i> analysis using Sitemap and subsequent docking analysis using Glide revealed two plausible binding sites for (–)-epicatechin. The study also investigated the crucial structural features required for activity, with a particular focus on the substitution pattern and hydroxyl group positions, which were found to be important for the activity. The study highlights the significance of computational approaches in targeting essential enzymes involved in bacterial peptidoglycan synthesis.</p><h3>Graphical abstract</h3>\\n <div><figure><div><div><picture><source><img></source></picture></div></div></figure></div>\\n </div>\",\"PeriodicalId\":621,\"journal\":{\"name\":\"Journal of Computer-Aided Molecular Design\",\"volume\":\"37 12\",\"pages\":\"721 - 733\"},\"PeriodicalIF\":3.0000,\"publicationDate\":\"2023-10-05\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of Computer-Aided Molecular Design\",\"FirstCategoryId\":\"99\",\"ListUrlMain\":\"https://link.springer.com/article/10.1007/s10822-023-00535-z\",\"RegionNum\":3,\"RegionCategory\":\"生物学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q3\",\"JCRName\":\"BIOCHEMISTRY & MOLECULAR BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Computer-Aided Molecular Design","FirstCategoryId":"99","ListUrlMain":"https://link.springer.com/article/10.1007/s10822-023-00535-z","RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q3","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
Mur ligase F as a new target for the flavonoids quercitrin, myricetin, and (–)-epicatechin
MurC, D, E, and F are ATP-dependent ligases involved in the stepwise assembly of the tetrapeptide stem of forming peptidoglycan. As highly conserved targets found exclusively in bacterial cells, they are of significant interest for antibacterial drug discovery. In this study, we employed a computer-aided molecular design approach to identify potential inhibitors of MurF. A biochemical inhibition assay was conducted, screening twenty-four flavonoids and related compounds against MurC-F, resulting in the identification of quercitrin, myricetin, and (–)-epicatechin as MurF inhibitors with IC50 values of 143 µM, 139 µM, and 92 µM, respectively. Notably, (–)-epicatechin demonstrated mixed type inhibition with ATP and uncompetitive inhibition with d-Ala-d-Ala dipeptide and UM3DAP substrates. Furthermore, in silico analysis using Sitemap and subsequent docking analysis using Glide revealed two plausible binding sites for (–)-epicatechin. The study also investigated the crucial structural features required for activity, with a particular focus on the substitution pattern and hydroxyl group positions, which were found to be important for the activity. The study highlights the significance of computational approaches in targeting essential enzymes involved in bacterial peptidoglycan synthesis.
期刊介绍:
The Journal of Computer-Aided Molecular Design provides a form for disseminating information on both the theory and the application of computer-based methods in the analysis and design of molecules. The scope of the journal encompasses papers which report new and original research and applications in the following areas:
- theoretical chemistry;
- computational chemistry;
- computer and molecular graphics;
- molecular modeling;
- protein engineering;
- drug design;
- expert systems;
- general structure-property relationships;
- molecular dynamics;
- chemical database development and usage.