Author:
Jiménez-Avalos Gabriel,Vargas-Ruiz A. Paula,Delgado-Pease Nicolás E.,Olivos-Ramirez Gustavo E.,Sheen Patricia,Fernández-Díaz Manolo,Quiliano Miguel,Zimic Mirko,Agurto-Arteaga Andres,Antiparra Ricardo,Ardiles-Reyes Manuel,Calderon Katherine,Cauna-Orocollo Yudith,de Grecia Cauti-Mendoza Maria,Chipana-Flores Naer,Choque-Guevara Ricardo,Chunga-Girón Xiomara,Criollo-Orozco Manuel,De La Cruz Lewis,Delgado-Ccancce Elmer,Elugo-Guevara Christian,Fernández-Sanchez Manolo,Guevara-Sarmiento Luis,Gutiérrez Kristel,Heredia-Almeyda Oscar,Huaccachi-Gonzalez Edison,Huerta-Roque Pedro,Icochea Eliana,Isasi-Rivas Gisela,Juscamaita-Bartra Romina A.,Licla-Inca Abraham,Montalvan Angela,Montesinos-Millan Ricardo,Núñez-Fernández Dennis,Ochoa-Ortiz Adiana,Páucar-Montoro Erika,Pauyac Kathy,Perez-Martinez Jose L.,Perez-M Norma,Poma-Acevedo Astrid,Quiñones-Garcia Stefany,Ramirez-Ortiz Ingrid,Ramos-Sono Daniel,Rios-Angulo Angela A.,Rios-Matos Dora,Rojas-Neyra Aldo,Romero Yomara K.,Salguedo-Bohorquez Mario I.,Sernaque-Aguilar Yacory,Soto Luis F.,Tataje-Lavanda Luis,Ticona Julio,Vallejos-Sánchez Katherine,Villanueva-Pérez Doris,Ygnacio-Aguirre Freddy,
Abstract
AbstractSARS-CoV-2 main protease is a common target for inhibition assays due to its high conservation among coronaviruses. Since flavonoids show antiviral activity, several in silico works have proposed them as potential SARS-CoV-2 main protease inhibitors. Nonetheless, there is reason to doubt certain results given the lack of consideration for flavonoid promiscuity or main protease plasticity, usage of short library sizes, absence of control molecules and/or the limitation of the methodology to a single target site. Here, we report a virtual screening study where dorsilurin E, euchrenone a11, sanggenol O and CHEMBL2171598 are proposed to inhibit main protease through different pathways. Remarkably, novel structural mechanisms were observed after sanggenol O and CHEMBL2171598 bound to experimentally proven allosteric sites. The former drastically affected the active site, while the latter triggered a hinge movement which has been previously reported for an inactive SARS-CoV main protease mutant. The use of a curated database of 4.8 k flavonoids, combining two well-known docking software (AutoDock Vina and AutoDock4.2), molecular dynamics and MMPBSA, guaranteed an adequate analysis and robust interpretation. These criteria can be considered for future screening campaigns against SARS-CoV-2 main protease.
Funder
Consejo Nacional de Ciencia, Tecnología e Innovación Tecnológica
Publisher
Springer Science and Business Media LLC