About: RNA-Dependent RNA Polymerase From SARS-CoV-2. Mechanism Of Reaction And Inhibition By Remdesivir

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An Entity of Type : schema:ScholarlyArticle, within Data Space : wasabi.inria.fr associated with source document(s)

Attributes	Values
type	Academic Article research paper schema:ScholarlyArticle
isDefinedBy	Covid-on-the-Web dataset
has title	RNA-Dependent RNA Polymerase From SARS-CoV-2. Mechanism Of Reaction And Inhibition By Remdesivir
Creator	Aranda, Juan Orozco, Modesto
Source	BioRxiv
abstract	We combine sequence analysis, molecular dynamics and hybrid quantum mechanics/molecular mechanics simulations to obtain the first description of the mechanism of reaction of SARS-CoV-2 RNA-dependent RNA polymerase (RdRp) and of the inhibition of the enzyme by Remdesivir. Despite its evolutionary youth, the enzyme is highly optimized to have good fidelity in nucleotide incorporation and a good catalytic efficiency. Our simulations strongly suggest that Remdesivir triphosphate (the active form of drug) is incorporated into the nascent RNA replacing ATP, leading to a duplex RNA which is structurally very similar to an unmodified one. We did not detect any reason to explain the inhibitory activity of Remdesivir at the active site. Displacement of the nascent Remdesivir-containing RNA duplex along the exit channel of the enzyme can occur without evident steric clashes which would justify delayed inhibition. However, after the incorporation of three more nucleotides we found a hydrated Serine which is placed in a perfect arrangement to react through a Pinner’s reaction with the nitrile group of Remdesivir. Kinetic barriers for crosslinking and polymerization are similar suggesting a competition between polymerization and inhibition. Analysis of SARS-CoV-2 mutational landscape and structural analysis of polymerases across different species support the proposed mechanism and suggest that virus has not explored yet resistance to Remdesivir inhibition.
has issue date	2020-06-21(xsd:dateTime)
bibo:doi	10.1101/2020.06.21.163592
has license	biorxiv
sha1sum (hex)	b966141fc83b035734cb3c41a165f2243dec8c3d
schema:url	https://doi.org/10.1101/2020.06.21.163592
resource representing a document's title	RNA-Dependent RNA Polymerase From SARS-CoV-2. Mechanism Of Reaction And Inhibition By Remdesivir
schema:publication	bioRxiv
resource representing a document's body	covid:b966141fc83b035734cb3c41a165f2243dec8c3d#body_text
is schema:about of	named entity 'SARS-CoV-2' named entity 'duplex' named entity 'inhibition' named entity 'enzyme' named entity 'resistance' named entity 'active form' named entity 'active site' named entity 'species' named entity 'nitrile' named entity 'RNA-DEPENDENT RNA POLYMERASE' named entity 'ITS' named entity 'REPLACING' named entity 'DETECT' named entity 'ACTIVE SITE' named entity 'COMPETITION' named entity 'MOLECULAR DYNAMICS' named entity 'SIMULATIONS' named entity 'ENZYME' named entity 'REMDESIVIR' named entity 'JUSTIFY' named entity 'simulations' named entity 'enzyme' named entity 'incorporation' named entity 'group' named entity 'react' named entity 'RNA' named entity 'Remdesivir' named entity 'hydrated' named entity 'reaction' named entity 'leading' named entity 'highly' named entity 'Remdesivir' named entity 'active site' named entity 'Remdesivir' named entity 'RNA duplex' named entity 'SARS-CoV-2' named entity 'Remdesivir' named entity 'Pinner' named entity 'enzyme' named entity 'nucleotides' named entity 'Remdesivir' named entity 'steric clashes' named entity 'virus' named entity 'RNA' named entity 'RNA' named entity 'RNA' named entity 'highly conserved' named entity 'RdRp' named entity 'molecule' named entity 'Arginine' named entity 'RTP' named entity 'helix' named entity 'RNA' named entity 'RdRp' named entity 'Ensembl' named entity 'enzyme' named entity 'RdRp' named entity 'SARS-CoV-2' named entity 'alpha helix' named entity 'transition states' named entity 'RNA' named entity 'substrate specificity' named entity 'Remdesivir' named entity 'RdRp' named entity 'thermalization' named entity 'RNA polymerase' named entity 'RNAs' named entity 'clinical trials' named entity 'proof-reading' named entity 'nucleophilic attack' named entity 'polymerization' named entity 'missense variant' named entity 'nucleotides' named entity 'viral protein' named entity 'QM/MM' named entity 'infectivity' named entity 'SARS-CoV-2' named entity 'protein' named entity 'phosphate groups' named entity 'B3LYP' named entity 'RdRp' named entity 'mutation' named entity 'Remdesivir'

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