Molecular characterization of ebselen binding activity to SARS-CoV-2 main protease

• Autores: Menéndez, Cintia Anabella; Byléhn, Fabian; Perez Lemus, Gustavo R.; Alvarado, Walter; de Pablo, Juan J.
• Año de publicación: 2020
• Idioma: inglés
• Tipo de recurso: artículo
• Materia: EBSELEN; SARS-COV-2; MOLECULAR DYNAMIC SIMULATION; COVID-19
• Institución: Consejo Nacional de Investigaciones Científicas y Técnicas

There is an urgent need to repurpose drugs against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Recent computational-experimental screenings have identified several existing drugs that could serve as effective inhibitors of the virus? main protease, Mpro, which is involved in gene expression and replication. Among these, ebselen (2-phenyl-1,2-benzoselenazol-3-one) appears to be particularly promising. Here, we examine, at a molecular level, the potential of ebselen to decrease Mpro activity. We find that it exhibits a distinct affinity for the catalytic region. Our results reveal a higher-affinity, previously unknown binding site localized between the II and III domains of the protein. A detailed strain analysis indicates that, on such a site, ebselen exerts a pronounced allosteric effect that regulates catalytic site access through surface-loop interactions, thereby inducing a reconfiguration of water hotspots. Together, these findings highlight the promise of ebselen as a repurposed drug against SARS-CoV-2.
Fil: Menéndez, Cintia Anabella. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Química del Sur. Universidad Nacional del Sur. Departamento de Química. Instituto de Química del Sur; Argentina
Fil: Byléhn, Fabian. University of Chicago; Estados Unidos
Fil: Perez Lemus, Gustavo R.. University of Chicago; Estados Unidos
Fil: Alvarado, Walter. University of Chicago; Estados Unidos
Fil: de Pablo, Juan J.. University of Chicago; Estados Unidos