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

Peralta-Moreno, M. N ; Mena, Y. ; Ortega-Alarcon, D. ; Jiménez-Alesanco, A. (Universidad de Zaragoza) ; Vega, S. ; Abian, O. (Universidad de Zaragoza) ; Velázquez-Campoy, A. (Universidad de Zaragoza) ; Thomson, T. M. ; Pinto, M. ; Granadino-Roldán, J. M. ; Tomás, M. ; Pérez, J. J. ; Rubio-Martínez, J.

Resumen: 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

Idioma: Inglés

DOI: 10.3390/ijms25116119

Año: 2024

Publicado en: International Journal of Molecular Sciences 25, 11 (2024), 6119 [17 pp.]
ISSN: 1661-6596

Financiación: info:eu-repo/grantAgreement/ES/DGA/B25-23R
Financiación: info:eu-repo/grantAgreement/ES/DGA/E45-23R
Financiación: info:eu-repo/grantAgreement/ES/ISCIII-FIS/PI18-00349
Financiación: info:eu-repo/grantAgreement/ES/ISCIII/PI21-00394
Financiación: info:eu-repo/grantAgreement/ES/MCIU-AEI-FEDER/BES-2017-080739
Financiación: info:eu-repo/grantAgreement/ES/MICINN/AEI/PID2021-127296OB-I00
Financiación: info:eu-repo/grantAgreement/ES/MICINN/CEX2021-001202-M
Financiación: info:eu-repo/grantAgreement/ES/MINECO/BFU2016-78232-P

Tipo y forma: Article (Published version)

Área (Departamento): Área Inmunología (Dpto. Microb.Ped.Radio.Sal.Pú.)
Área (Departamento): Área Bioquímica y Biolog.Mole. (Dpto. Bioq.Biolog.Mol. Celular)