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https://doi.org/10.26434/chemr...
Article . 2021 . Peer-reviewed
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Article . 2021
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Journal of Computer-Aided Molecular Design
Article . 2021 . Peer-reviewed
License: Springer TDM
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Target identification for repurposed drugs active against SARS-CoV-2 via high-throughput inverse docking

Authors: Marcos Ariel Villarreal; Marcos Ariel Villarreal; S. Alexis Paz; S. Alexis Paz; Cameron F. Abrams; Sergio P. Ribone; Sergio P. Ribone;

Target identification for repurposed drugs active against SARS-CoV-2 via high-throughput inverse docking

Abstract

Screening already approved drugs for activity against a novel pathogen can be an important part of global rapid-response strategies in pandemics. Such high-throughput repurposing screens have already identified several existing drugs with potential to combat SARS-CoV-2. However, moving these hits forward for possible development into drugs specifically against this pathogen requires unambiguous identification of their corresponding targets, something the high-throughput screens are not typically designed to reveal. We present here a new computational inverse-docking protocol that uses all-atom protein structures and a combination of docking methods to rank-order targets for each of several existing drugs for which a plurality of recent high-throughput screens detected anti-SARS-CoV-2 activity. We demonstrate validation of this method with known drug-target pairs. We subjected 152 distinct drugs potentially suitable for repurposing to the inverse docking procedure. Detailed structural analysis revealed important insights and could potentially lead to more rational design of new drugs against these targets.

Keywords

SARS-COV-2, Molecular Dynamics Simulation, HIGH-THROUGHPUT, Antiviral Agents, Article, REPURPOSING, https://purl.org/becyt/ford/1.4, Humans, Protease Inhibitors, INVERSE DOCKING, https://purl.org/becyt/ford/1, TMPRSS2, SARS-CoV-2, Serine Endopeptidases, Drug Repositioning, COVID-19, PIKfyve, COVID-19 Drug Treatment, Molecular Docking Simulation, Pharmaceutical Preparations

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    citations
    This is an alternative to the "Influence" indicator, which also reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).
    6
    popularity
    This indicator reflects the "current" impact/attention (the "hype") of an article in the research community at large, based on the underlying citation network.
    Top 10%
    influence
    This indicator reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).
    Average
    impulse
    This indicator reflects the initial momentum of an article directly after its publication, based on the underlying citation network.
    Top 10%
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citations
This is an alternative to the "Influence" indicator, which also reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).
BIP!Citations provided by BIP!
popularity
This indicator reflects the "current" impact/attention (the "hype") of an article in the research community at large, based on the underlying citation network.
BIP!Popularity provided by BIP!
influence
This indicator reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).
BIP!Influence provided by BIP!
impulse
This indicator reflects the initial momentum of an article directly after its publication, based on the underlying citation network.
BIP!Impulse provided by BIP!
6
Top 10%
Average
Top 10%
Green
hybrid