Allosteric hotspots in the main protease of SARS-CoV-2
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Published version
Author(s)
Strömich, Léonie
Wu, Nan
Barahona, Mauricio
Yaliraki, Sophia
Type
Journal Article
Abstract
Inhibiting the main protease of SARS-CoV-2 is of great interest in tackling the COVID-19 pandemic caused by the virus. Most efforts have been centred on inhibiting the binding site of the enzyme. However, considering allosteric sites, distant from the active or orthosteric site, broadens the search space for drug candidates and confers the advantages of allosteric drug targeting. Here, we report the allosteric communication pathways in the main protease dimer by using two novel fully atomistic graph-theoretical methods: Bond-to-bond propensity, which has been previously successful in identifying allosteric sites in extensive benchmark data sets without a priori knowledge, and Markov transient analysis, which has previously aided in finding novel drug targets in catalytic protein families. Using statistical bootstrapping, we score the highest ranking sites against random sites at similar distances, and we identify four statistically significant putative allosteric sites as good candidates for alternative drug targeting.
Date Issued
2022-09-15
Date Acceptance
2022-07-12
Citation
Journal of Molecular Biology, 2022, 434 (17)
ISSN
0022-2836
Publisher
Elsevier
Journal / Book Title
Journal of Molecular Biology
Volume
434
Issue
17
Copyright Statement
© 2022 The Authors. Published by Elsevier Ltd.This is an open access article under the CC BY license http://creativecommons.org/licenses/by/4.0/).
Sponsor
Engineering & Physical Science Research Council (EPSRC)
Grant Number
EP/N014529/1
Subjects
Science & Technology
Life Sciences & Biomedicine
Biochemistry & Molecular Biology
graph theory
allosteric site prediction
atomistic graph representation
SARS-CoV-2
3C-LIKE PROTEASE
SARS
DESIGN
REVEALS
COMPLEX
PREDICTION
PROTEINS
TARGET
SITES
FORCE
SARS-CoV-2
allosteric site prediction
atomistic graph representation
graph theory
Allosteric Site
Coronavirus 3C Proteases
Molecular Docking Simulation
Protein Conformation
Allosteric Site
Protein Conformation
Molecular Docking Simulation
Coronavirus 3C Proteases
Biochemistry & Molecular Biology
0304 Medicinal and Biomolecular Chemistry
0601 Biochemistry and Cell Biology
0605 Microbiology
Publication Status
Published
Article Number
ARTN 167748
Date Publish Online
2022-07-16