Comprehensive virtual screening of 4.8 k flavonoids reveals novel insights into allosteric inhibition of SARS-CoV-2 MPRO
Gabriel Jiménez-Avalos, A. Paula Vargas-Ruiz, Nicolás E. Delgado-Pease, Gustavo E. Olivos-Ramírez, Patricia Sheen, Manolo Fernández‐Díaz, Miguel Quiliano, Mirko Zimic, COVID-19 Working Group in Perú, Andrés Agurto-Arteaga, Ricardo Antiparra, Manuel Ardiles-Reyes, Katherine Calderón, Yudith Cauna-Orocollo, Maria De Grecia Cauti Mendoza, Naer Chipana-Flores, Ricardo Choque-Guevara, Xiomara Chunga-Girón, Manuel Criollo-Orozco, Lewis De La Cruz, Elmer Delgado-Ccancce, Christian Elugo-Guevara, Manolo Fernández-Sánchez, Luis A. Guevara-Sarmiento, Kristel Gutiérrez, Oscar Heredia-Almeyda, Edison Huaccachi-Gonzalez, Pedro Huerta-Roque, Eliana Icochea D., Gisela Isasi-Rivas, Romina A. Juscamaita-Bartra, Abraham Licla-Inca, Ángela Montalván-Ávalos, Ricardo Montesinos, Dennis Fernandez, Adiana Ochoa-Ortiz, Erika Páucar-Montoro, Kathy Pauyac, Jose L. Perez-Martinez, Norma Perez-M, Astrid Poma-Acevedo, Stefany Quiñones-García, Ingrid Ramirez-Ortiz, Daniel Ramos‐Sono, Angela Rios-Angulo, Dora Ríos-Matos, Aldo Rojas-Neyra, Yomara K. Romero, Mario I. Salguedo-Bohorquez, Yacory Sernaque-Aguilar, Luis F. Soto, Luis Tataje‐Lavanda, Julio Ticona, Katherine Vallejos-Sánchez, Doris Villanueva-Pérez, Freddy Ygnacio-Aguirre
Abstract
SARS-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.