136106 20260217205550.0 doi 10.3390/ijms25116119 sideral 139033 ART-2024-139033 eng Peralta-Moreno, M. N Shedding Light on Dark Chemical Matter: The Discovery of a SARS-CoV-2 Mpro Main Protease Inhibitor through Intensive Virtual Screening and In Vitro Evaluation 2024 Access copy available to the general public Unrestricted The development of specific antiviral therapies targeting SARS-CoV-2 remains fundamental because of the continued high incidence of COVID-19 and limited accessibility to antivirals in some countries. In this context, dark chemical matter (DCM), a set of drug-like compounds with outstanding selectivity profiles that have never shown bioactivity despite being extensively assayed, appears to be an excellent starting point for drug development. Accordingly, in this study, we performed a high-throughput screening to identify inhibitors of the SARS-CoV-2 main protease (Mpro) using DCM compounds as ligands. Multiple receptors and two different docking scoring functions were employed to identify the best molecular docking poses. The selected structures were subjected to extensive conventional and Gaussian accelerated molecular dynamics. From the results, four compounds with the best molecular behavior and binding energy were selected for experimental testing, one of which presented inhibitory activity with a Ki value of 48 ± 5 μM. Through virtual screening, we identified a significant starting point for drug development, shedding new light on DCM compounds info:eu-repo/grantAgreement/ES/DGA/B25-23R info:eu-repo/grantAgreement/ES/DGA/E45-23R info:eu-repo/grantAgreement/ES/ISCIII-FIS/PI18-00349 info:eu-repo/grantAgreement/ES/ISCIII/PI21-00394 info:eu-repo/grantAgreement/ES/MCIU-AEI-FEDER/BES-2017-080739 info:eu-repo/grantAgreement/ES/MICINN/AEI/PID2021-127296OB-I00 info:eu-repo/grantAgreement/ES/MICINN/CEX2021-001202-M info:eu-repo/grantAgreement/ES/MINECO/BFU2016-78232-P info:eu-repo/semantics/openAccess by https://creativecommons.org/licenses/by/4.0/deed.es 4.9 2024 BIOCHEMISTRY & MOLECULAR BIOLOGY 72 / 320 = 0.225 2024 Q1 T1 CHEMISTRY, MULTIDISCIPLINARY 70 / 239 = 0.293 2024 Q2 T1 1.273 2024 Medicine (miscellaneous) 2024 Q1 Physical and Theoretical Chemistry 2024 Q1 Computer Science Applications 2024 Q1 Inorganic Chemistry 2024 Q1 Spectroscopy 2024 Q1 Organic Chemistry 2024 Q1 Molecular Biology 2024 Q2 Catalysis 2024 Q2 9.0 2024 info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion Mena, Y. Ortega-Alarcon, D. (orcid)0000-0003-1885-4365 Jiménez-Alesanco, A. Universidad de Zaragoza (orcid)0000-0003-4726-7821 Vega, S. (orcid)0000-0002-1232-6310 Abian, O. Universidad de Zaragoza (orcid)0000-0001-5664-1729 Velázquez-Campoy, A. Universidad de Zaragoza (orcid)0000-0001-5702-4538 Thomson, T. M. Pinto, M. Granadino-Roldán, J. M. Tomás, M. Pérez, J. J. Rubio-Martínez, J. 1011 566 Universidad de Zaragoza Dpto. Microb.Ped.Radio.Sal.Pú. Área Inmunología 1002 060 Universidad de Zaragoza Dpto. Bioq.Biolog.Mol. Celular Área Bioquímica y Biolog.Mole. 25, 11 (2024), 6119 [17 pp.] Int. j. mol. sci. International Journal of Molecular Sciences 1661-6596 2010873 http://zaguan.unizar.es/record/136106/files/texto_completo.pdf Versión publicada 2658816 http://zaguan.unizar.es/record/136106/files/texto_completo.jpg?subformat=icon icon Versión publicada oai:zaguan.unizar.es:136106 articulos driver 2026-02-17-20:39:54 ARTICLE