Abstract:Most recently, an outbreak of severe pneumonia caused by the infection of SARS-CoV-2, a novel coronavirus first identified in Wuhan, China, imposes serious threats to public health. Upon infecting host cells, coronaviruses assemble a multi-subunit RNA-synthesis complex of viral non-structural proteins (nsp) responsible for the replication and transcription of the viral genome. Therefore, the role and inhibition of nsp12 are indispensable. A cryo-EM structure of RdRp from SARs-CoV-2 was used to identify novel d… Show more
“…Cys141 and His41 residue forms a catalytic dyad on the active site of the protein essential for its catalytic function. Similar results were recently obtained by molecular docking with different molecules against the Mpro protein [57,59,60]. Quercetin 3-Rhamnose, a flavonol with a rhamnose at position 3 of the C ring, is involved in several hydrogen bonds contracted with Thr26, Phe140, Leu141 and Gly143 (Fig 5A).…”
A novel coronavirus responsible of acute respiratory infection closely related to SARS-CoV has recently emerged. So far there is no consensus for drug treatment to stop the spread of the virus. Discovery of a drug that would limit the virus expansion is one of the biggest challenges faced by the humanity in the last decades. In this perspective, to test existing drugs as inhibitors of SARS-CoV-2 main protease is a good approach. Among natural phenolic compounds found in plants, fruit, and vegetables; flavonoids are the most abundant. Flavonoids, especially in their glycosylated forms, display a number of physiological activities, which makes them interesting to investigate as antiviral molecules. The flavonoids chemical structures were downloaded from PubChem and protease structure 6LU7 was from the Protein Data Bank site. Molecular docking study was performed using AutoDock Vina. Among the tested molecules Quercetin-3-O-rhamnoside showed the highest binding affinity (-9,7 kcal/mol). Docking studies showed that glycosylated flavonoids are good inhibitors for the SARS-CoV-2 protease and could be further investigated by in vitro and in vivo experiments for further validation. MD simulations were further performed to evaluate the dynamic behavior and stability of the protein in complex with the three best hits of docking experiments. Our results indicate that the rutin is a potential drug to inhibit the function of Chymotrypsin-like protease (3CL pro) of Coronavirus.
“…Cys141 and His41 residue forms a catalytic dyad on the active site of the protein essential for its catalytic function. Similar results were recently obtained by molecular docking with different molecules against the Mpro protein [57,59,60]. Quercetin 3-Rhamnose, a flavonol with a rhamnose at position 3 of the C ring, is involved in several hydrogen bonds contracted with Thr26, Phe140, Leu141 and Gly143 (Fig 5A).…”
A novel coronavirus responsible of acute respiratory infection closely related to SARS-CoV has recently emerged. So far there is no consensus for drug treatment to stop the spread of the virus. Discovery of a drug that would limit the virus expansion is one of the biggest challenges faced by the humanity in the last decades. In this perspective, to test existing drugs as inhibitors of SARS-CoV-2 main protease is a good approach. Among natural phenolic compounds found in plants, fruit, and vegetables; flavonoids are the most abundant. Flavonoids, especially in their glycosylated forms, display a number of physiological activities, which makes them interesting to investigate as antiviral molecules. The flavonoids chemical structures were downloaded from PubChem and protease structure 6LU7 was from the Protein Data Bank site. Molecular docking study was performed using AutoDock Vina. Among the tested molecules Quercetin-3-O-rhamnoside showed the highest binding affinity (-9,7 kcal/mol). Docking studies showed that glycosylated flavonoids are good inhibitors for the SARS-CoV-2 protease and could be further investigated by in vitro and in vivo experiments for further validation. MD simulations were further performed to evaluate the dynamic behavior and stability of the protein in complex with the three best hits of docking experiments. Our results indicate that the rutin is a potential drug to inhibit the function of Chymotrypsin-like protease (3CL pro) of Coronavirus.
“…Inhibitors may be designed to block the ssRNA binding N-NTD site. Binding of drugs at protein interfaces is mostly controlled by some specific residues contributing disproportionately to the Gibbs free energy of binding and dynamics of proteins (Massova and Kollman 1999 ; Weiss et al 2000 ; Arkin and Wells 2004 ; Zhao and Chmielewski 2005 ; Moreira et al 2007 ; Wells and McClendon 2007 ; Boukharta et al 2014 ; Ibarra et al 2019 ; Khan et al 2020a ). Fig.…”
Severe acute respiratory syndrome virus 2 (SARS-CoV-2) belongs to the single-stranded positive-sense RNA family. The virus contains a large genome that encodes four structural proteins, small envelope (E), matrix (M), nucleocapsid phosphoprotein (N), spike (S), and 16 nonstructural proteins (nsp1-16) that together, ensure replication of the virus in the host cell. Among these proteins, the interactions of N and Nsp3 are essential that links the viral genome for processing. The N proteins reside at CoV RNA synthesis sites known as the replication-transcription complexes (RTCs). The N-terminal of N has RNA-binding domain (N-NTD), capturing the RNA genome while the C-terminal domain (N-CTD) anchors the viral Nsp3, a component of RTCs. Although the structural information has been recently released, the residues involved in contacts between N-CTD with Nsp3 are Communicated by Erko Stackebrandt.
“…With unavailability of specific vaccines and medicines, antiviral, antimalarial drugs and convalescent plasma therapy are being used as primary treatment (Duan et al 2020 ; Mitjà and Clotet 2020 ; Vincent et al 2005 ). Furthermore, researchers have screened molecular databases of natural products, marine natural compounds, and previously reported virus inhibitors from terrestrial fungi against various SARS-CoV-2 proteins (Khan et al 2020a , b ; Quimque et al 2020 ) along with drug repurposing (Khan et al 2020c ; Maurya et al 2020 ). To find an effective treatment, researchers have identified potential protein targets of the virus.…”
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