Julia J. Liang , Eleni Pitsillou , Hannah L.Y. Lau , Cian P. Mccubbery , Hockxuen Gan , Andrew Hung , Tom C. Karagiannis
{"title":"利用 EpiMed Coronabank 化学物质库鉴定潜在的 SARS-CoV-2 抗病毒药物：针对 nsp14 ExoN 结构域和 PLpro 萘结合位点的硅学研究","authors":"Julia J. Liang , Eleni Pitsillou , Hannah L.Y. Lau , Cian P. Mccubbery , Hockxuen Gan , Andrew Hung , Tom C. Karagiannis","doi":"10.1016/j.jmgm.2024.108803","DOIUrl":null,"url":null,"abstract":"<div><p>The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) genome encodes 29 proteins including four structural, 16 nonstructural (nsps), and nine accessory proteins (<span>https://epimedlab.org/sars-cov-2-proteome/</span><svg><path></path></svg>). Many of these proteins contain potential targetable sites for the development of antivirals. Despite the widespread use of vaccinations, the emergence of variants necessitates the investigation of new therapeutics and antivirals. Here, the EpiMed Coronabank Chemical Collection (<span>https://epimedlab.org/crl/</span><svg><path></path></svg>) was utilized to investigate potential antivirals against the nsp14 exoribonuclease (ExoN) domain. Molecular docking was performed to evaluate the binding characteristics of our chemical library against the nsp14 ExoN site. Based on the initial screen, trisjuglone, ararobinol, corilagin, and naphthofluorescein were identified as potential lead compounds. Molecular dynamics (MD) simulations were subsequently performed, with the results highlighting the stability of the lead compounds in the nsp14 ExoN site. Protein-RNA docking revealed the potential for the lead compounds to disrupt the interaction with RNA when bound to the ExoN site. Moreover, hypericin, cyanidin-3-O-glucoside, and rutin were previously identified as lead compounds targeting the papain-like protease (PL<sup>pro</sup>) naphthalene binding site. Through performing MD simulations, the stability and interactions of lead compounds with PL<sup>pro</sup> were further examined. Overall, given the critical role of the exonuclease activity of nsp14 in ensuring viral fidelity and the multifunctional role of PL<sup>pro</sup> in viral pathobiology and replication, these nsps represent important targets for antiviral drug development. Our databases can be utilized for <em>in silico</em> studies, such as the ones performed here, and this approach can be applied to other potentially druggable SARS-CoV-2 protein targets.</p></div>","PeriodicalId":16361,"journal":{"name":"Journal of molecular graphics & modelling","volume":"131 ","pages":"Article 108803"},"PeriodicalIF":2.7000,"publicationDate":"2024-05-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1093326324001037/pdfft?md5=e210d9241884d3cecf0ed92a828f7a38&pid=1-s2.0-S1093326324001037-main.pdf","citationCount":"0","resultStr":"{\"title\":\"Utilization of the EpiMed Coronabank Chemical Collection to identify potential SARS-CoV-2 antivirals: in silico studies targeting the nsp14 ExoN domain and PLpro naphthalene binding site\",\"authors\":\"Julia J. Liang , Eleni Pitsillou , Hannah L.Y. Lau , Cian P. Mccubbery , Hockxuen Gan , Andrew Hung , Tom C. Karagiannis\",\"doi\":\"10.1016/j.jmgm.2024.108803\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><p>The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) genome encodes 29 proteins including four structural, 16 nonstructural (nsps), and nine accessory proteins (<span>https://epimedlab.org/sars-cov-2-proteome/</span><svg><path></path></svg>). Many of these proteins contain potential targetable sites for the development of antivirals. Despite the widespread use of vaccinations, the emergence of variants necessitates the investigation of new therapeutics and antivirals. Here, the EpiMed Coronabank Chemical Collection (<span>https://epimedlab.org/crl/</span><svg><path></path></svg>) was utilized to investigate potential antivirals against the nsp14 exoribonuclease (ExoN) domain. Molecular docking was performed to evaluate the binding characteristics of our chemical library against the nsp14 ExoN site. Based on the initial screen, trisjuglone, ararobinol, corilagin, and naphthofluorescein were identified as potential lead compounds. Molecular dynamics (MD) simulations were subsequently performed, with the results highlighting the stability of the lead compounds in the nsp14 ExoN site. Protein-RNA docking revealed the potential for the lead compounds to disrupt the interaction with RNA when bound to the ExoN site. Moreover, hypericin, cyanidin-3-O-glucoside, and rutin were previously identified as lead compounds targeting the papain-like protease (PL<sup>pro</sup>) naphthalene binding site. Through performing MD simulations, the stability and interactions of lead compounds with PL<sup>pro</sup> were further examined. Overall, given the critical role of the exonuclease activity of nsp14 in ensuring viral fidelity and the multifunctional role of PL<sup>pro</sup> in viral pathobiology and replication, these nsps represent important targets for antiviral drug development. Our databases can be utilized for <em>in silico</em> studies, such as the ones performed here, and this approach can be applied to other potentially druggable SARS-CoV-2 protein targets.</p></div>\",\"PeriodicalId\":16361,\"journal\":{\"name\":\"Journal of molecular graphics & modelling\",\"volume\":\"131 \",\"pages\":\"Article 108803\"},\"PeriodicalIF\":2.7000,\"publicationDate\":\"2024-05-26\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.sciencedirect.com/science/article/pii/S1093326324001037/pdfft?md5=e210d9241884d3cecf0ed92a828f7a38&pid=1-s2.0-S1093326324001037-main.pdf\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of molecular graphics & modelling\",\"FirstCategoryId\":\"99\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S1093326324001037\",\"RegionNum\":4,\"RegionCategory\":\"生物学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"BIOCHEMICAL RESEARCH METHODS\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of molecular graphics & modelling","FirstCategoryId":"99","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S1093326324001037","RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"BIOCHEMICAL RESEARCH METHODS","Score":null,"Total":0}
Utilization of the EpiMed Coronabank Chemical Collection to identify potential SARS-CoV-2 antivirals: in silico studies targeting the nsp14 ExoN domain and PLpro naphthalene binding site
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) genome encodes 29 proteins including four structural, 16 nonstructural (nsps), and nine accessory proteins (https://epimedlab.org/sars-cov-2-proteome/). Many of these proteins contain potential targetable sites for the development of antivirals. Despite the widespread use of vaccinations, the emergence of variants necessitates the investigation of new therapeutics and antivirals. Here, the EpiMed Coronabank Chemical Collection (https://epimedlab.org/crl/) was utilized to investigate potential antivirals against the nsp14 exoribonuclease (ExoN) domain. Molecular docking was performed to evaluate the binding characteristics of our chemical library against the nsp14 ExoN site. Based on the initial screen, trisjuglone, ararobinol, corilagin, and naphthofluorescein were identified as potential lead compounds. Molecular dynamics (MD) simulations were subsequently performed, with the results highlighting the stability of the lead compounds in the nsp14 ExoN site. Protein-RNA docking revealed the potential for the lead compounds to disrupt the interaction with RNA when bound to the ExoN site. Moreover, hypericin, cyanidin-3-O-glucoside, and rutin were previously identified as lead compounds targeting the papain-like protease (PLpro) naphthalene binding site. Through performing MD simulations, the stability and interactions of lead compounds with PLpro were further examined. Overall, given the critical role of the exonuclease activity of nsp14 in ensuring viral fidelity and the multifunctional role of PLpro in viral pathobiology and replication, these nsps represent important targets for antiviral drug development. Our databases can be utilized for in silico studies, such as the ones performed here, and this approach can be applied to other potentially druggable SARS-CoV-2 protein targets.
期刊介绍：
The Journal of Molecular Graphics and Modelling is devoted to the publication of papers on the uses of computers in theoretical investigations of molecular structure, function, interaction, and design. The scope of the journal includes all aspects of molecular modeling and computational chemistry, including, for instance, the study of molecular shape and properties, molecular simulations, protein and polymer engineering, drug design, materials design, structure-activity and structure-property relationships, database mining, and compound library design.
As a primary research journal, JMGM seeks to bring new knowledge to the attention of our readers. As such, submissions to the journal need to not only report results, but must draw conclusions and explore implications of the work presented. Authors are strongly encouraged to bear this in mind when preparing manuscripts. Routine applications of standard modelling approaches, providing only very limited new scientific insight, will not meet our criteria for publication. Reproducibility of reported calculations is an important issue. Wherever possible, we urge authors to enhance their papers with Supplementary Data, for example, in QSAR studies machine-readable versions of molecular datasets or in the development of new force-field parameters versions of the topology and force field parameter files. Routine applications of existing methods that do not lead to genuinely new insight will not be considered.
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