Comprehensive virtual screening of 4.8 k flavonoids reveals novel insights into allosteric inhibition of SARS-CoV-2 M
Antiviral Agents
/ pharmacology
Binding Sites
COVID-19
/ immunology
Coronavirus 3C Proteases
/ antagonists & inhibitors
Databases, Factual
Flavonoids
/ pharmacology
Humans
Molecular Docking Simulation
Molecular Dynamics Simulation
Protease Inhibitors
/ pharmacology
Protein Binding
SARS-CoV-2
/ drug effects
COVID-19 Drug Treatment
Journal
Scientific reports
ISSN: 2045-2322
Titre abrégé: Sci Rep
Pays: England
ID NLM: 101563288
Informations de publication
Date de publication:
29 07 2021
29 07 2021
Historique:
received:
11
02
2021
accepted:
29
06
2021
entrez:
30
7
2021
pubmed:
31
7
2021
medline:
17
8
2021
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 34326429
doi: 10.1038/s41598-021-94951-6
pii: 10.1038/s41598-021-94951-6
pmc: PMC8322093
doi:
Substances chimiques
Antiviral Agents
0
Flavonoids
0
Protease Inhibitors
0
sanggenon O
0
3C-like proteinase, SARS-CoV-2
EC 3.4.22.-
Coronavirus 3C Proteases
EC 3.4.22.28
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
15452Subventions
Organisme : Consejo Nacional de Ciencia, Tecnología e Innovación Tecnológica
ID : 048-2020
Investigateurs
Andres Agurto-Arteaga
(A)
Ricardo Antiparra
(R)
Manuel Ardiles-Reyes
(M)
Katherine Calderon
(K)
Yudith Cauna-Orocollo
(Y)
Maria de Grecia Cauti-Mendoza
(M)
Naer Chipana-Flores
(N)
Ricardo Choque-Guevara
(R)
Xiomara Chunga-Girón
(X)
Manuel Criollo-Orozco
(M)
Lewis De La Cruz
(L)
Elmer Delgado-Ccancce
(E)
Christian Elugo-Guevara
(C)
Manolo Fernández-Sanchez
(M)
Luis Guevara-Sarmiento
(L)
Kristel Gutiérrez
(K)
Oscar Heredia-Almeyda
(O)
Edison Huaccachi-Gonzalez
(E)
Pedro Huerta-Roque
(P)
Eliana Icochea
(E)
Gisela Isasi-Rivas
(G)
Romina A Juscamaita-Bartra
(RA)
Abraham Licla-Inca
(A)
Angela Montalvan
(A)
Ricardo Montesinos-Millan
(R)
Dennis Núñez-Fernández
(D)
Adiana Ochoa-Ortiz
(A)
Erika Páucar-Montoro
(E)
Kathy Pauyac
(K)
Jose L Perez-Martinez
(JL)
Norma Perez-M
(N)
Astrid Poma-Acevedo
(A)
Stefany Quiñones-Garcia
(S)
Ingrid Ramirez-Ortiz
(I)
Daniel Ramos-Sono
(D)
Angela A Rios-Angulo
(AA)
Dora Rios-Matos
(D)
Aldo Rojas-Neyra
(A)
Yomara K Romero
(YK)
Mario I Salguedo-Bohorquez
(MI)
Yacory Sernaque-Aguilar
(Y)
Luis F Soto
(LF)
Luis Tataje-Lavanda
(L)
Julio Ticona
(J)
Katherine Vallejos-Sánchez
(K)
Doris Villanueva-Pérez
(D)
Freddy Ygnacio-Aguirre
(F)
Informations de copyright
© 2021. The Author(s).
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