{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T01:05:03Z","timestamp":1760231103675,"version":"build-2065373602"},"reference-count":36,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2022,8,29]],"date-time":"2022-08-29T00:00:00Z","timestamp":1661731200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Agencia Estatal de Investigaci\u00f3n, Ministerio de Ciencia e Innovacion","award":["PID2020-15747RB-I00\/AEI\/10.13039"],"award-info":[{"award-number":["PID2020-15747RB-I00\/AEI\/10.13039"]}]},{"name":"European Union\u2014NextGenerationEU","award":["PID2020-15747RB-I00\/AEI\/10.13039"],"award-info":[{"award-number":["PID2020-15747RB-I00\/AEI\/10.13039"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Toxins"],"abstract":"<jats:p>In the work described here, a number of sesquiterpenes and benzoxazinoids from natural sources, along with their easily accessible derivatives, were evaluated against the main protease, RNA replicase and spike glycoprotein of SARS-CoV-2 by molecular docking. These natural products and their derivatives have previously shown remarkable antiviral activities. The most relevant compounds were the 4-fluoro derivatives of santamarine, reynosin and 2-amino-3H-phenoxazin-3-one in terms of the docking score. Those compounds fulfill the Lipinski\u2019s rule, so they were selected for the analysis by molecular dynamics, and the kinetic stabilities of the complexes were assessed. The addition of the 4-fluorobenzoate fragment to the natural products enhances their potential against all of the proteins tested, and the complex stability after 50 ns validates the inhibition calculated. The derivatives prepared from reynosin and 2-amino-3H-phenoxazin-3-one are able to generate more hydrogen bonds with the Mpro, thus enhancing the stability of the protein\u2013ligand and generating a long-term complex for inhibition. The 4-fluoro derivate of santamarine and reynosin shows to be really active against the spike protein, with the RMSD site fluctuation lower than 1.5 \u00c5. Stabilization is mainly achieved by the hydrogen-bond interactions, and the stabilization is improved by the 4-fluorobenzoate fragment being added. Those compounds tested in silico reach as candidates from natural sources to fight this virus, and the results concluded that the addition of the 4-fluorobenzoate fragment to the natural products enhances their inhibition potential against the main protease, RNA replicase and spike protein of SARS-CoV-2.<\/jats:p>","DOI":"10.3390\/toxins14090599","type":"journal-article","created":{"date-parts":[[2022,8,31]],"date-time":"2022-08-31T02:09:36Z","timestamp":1661911776000},"page":"599","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["In Silico Evaluation of Sesquiterpenes and Benzoxazinoids Phytotoxins against Mpro, RNA Replicase and Spike Protein of SARS-CoV-2 by Molecular Dynamics. Inspired by Nature"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6952-2964","authenticated-orcid":false,"given":"Francisco J. R.","family":"Mej\u00edas","sequence":"first","affiliation":[{"name":"Allelopathy Group, Department of Organic Chemistry, Institute of Biomolecules (INBIO), Campus CEIA3, School of Science, University of C\u00e1diz, C\/Rep\u00fablica Saharaui, 7, 11510 Puerto Real, Spain"},{"name":"Center for Molecular Biosciences (CMBI), Institute of Pharmacy\/Pharmacognosy, University of Innsbruck, 6020 Innsbruck, Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9799-0850","authenticated-orcid":false,"given":"Alexandra G.","family":"Dur\u00e1n","sequence":"additional","affiliation":[{"name":"Allelopathy Group, Department of Organic Chemistry, Institute of Biomolecules (INBIO), Campus CEIA3, School of Science, University of C\u00e1diz, C\/Rep\u00fablica Saharaui, 7, 11510 Puerto Real, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6659-373X","authenticated-orcid":false,"given":"Nuria","family":"Chinchilla","sequence":"additional","affiliation":[{"name":"Allelopathy Group, Department of Organic Chemistry, Institute of Biomolecules (INBIO), Campus CEIA3, School of Science, University of C\u00e1diz, C\/Rep\u00fablica Saharaui, 7, 11510 Puerto Real, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3616-9134","authenticated-orcid":false,"given":"Rosa M.","family":"Varela","sequence":"additional","affiliation":[{"name":"Allelopathy Group, Department of Organic Chemistry, Institute of Biomolecules (INBIO), Campus CEIA3, School of Science, University of C\u00e1diz, C\/Rep\u00fablica Saharaui, 7, 11510 Puerto Real, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jos\u00e9 A.","family":"\u00c1lvarez","sequence":"additional","affiliation":[{"name":"Department of Physical Chemistry, Faculty of Sciences, INBIO, University of C\u00e1diz, 11510 Puerto Real, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7844-9401","authenticated-orcid":false,"given":"Jos\u00e9 M. G.","family":"Molinillo","sequence":"additional","affiliation":[{"name":"Allelopathy Group, Department of Organic Chemistry, Institute of Biomolecules (INBIO), Campus CEIA3, School of Science, University of C\u00e1diz, C\/Rep\u00fablica Saharaui, 7, 11510 Puerto Real, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3720-259X","authenticated-orcid":false,"given":"Francisco","family":"Garc\u00eda-Cozar","sequence":"additional","affiliation":[{"name":"Department of Biomedicine, Biotechnology and Public Health, University of C\u00e1diz and Institute of Biomedical Research C\u00e1diz (INIBICA), 11009 C\u00e1diz, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8862-2864","authenticated-orcid":false,"given":"Francisco A.","family":"Mac\u00edas","sequence":"additional","affiliation":[{"name":"Allelopathy Group, Department of Organic Chemistry, Institute of Biomolecules (INBIO), Campus CEIA3, School of Science, University of C\u00e1diz, C\/Rep\u00fablica Saharaui, 7, 11510 Puerto Real, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,8,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"4030","DOI":"10.4049\/jimmunol.173.6.4030","article-title":"Mechanisms of Host Defense Following Severe Acute Respiratory Syndrome-Coronavirus (SARS-CoV) Pulmonary Infection of Mice","volume":"173","author":"Glass","year":"2004","journal-title":"J. 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