The Discovery of Small Allosteric and Active Site Inhibitors of the SARS-CoV-2 Main Protease via Structure-Based Virtual Screening and Biological Evaluation

The main protease enzyme (Mpro) of SARS-CoV-2 is one of the most promising targets for COVID-19 treatment. Accordingly, in this work, a structure-based virtual screening of 3.8 million ligand libraries was carried out. After rigorous filtering, docking, and post screening assessments, 78 compounds w...

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Published inMolecules (Basel, Switzerland) Vol. 27; no. 19; p. 6710
Main Authors Mahgoub, Radwa E, Mohamed, Feda E, Alzyoud, Lara, Ali, Bassam R, Ferreira, Juliana, Rabeh, Wael M, AlNeyadi, Shaikha S, Atatreh, Noor, Ghattas, Mohammad A
Format Journal Article
LanguageEnglish
Published Basel MDPI AG 01.10.2022
MDPI
Subjects
allosteric inhibitor
Allosteric properties
aryl nitrile
Binding sites
Coronaviruses
COVID-19
docking
Efficiency
Enzymes
Epidemics
Evaluation
Health aspects
Inhibitors
Libraries
Ligands
Middle East respiratory syndrome
Molecular weight
Mpro
Protease
Proteinase
Respiratory diseases
SARS-CoV-2
Severe acute respiratory syndrome
Severe acute respiratory syndrome coronavirus 2
Simulation
structure-based virtual screening
United Arab Emirates
Middle East
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Summary:The main protease enzyme (Mpro) of SARS-CoV-2 is one of the most promising targets for COVID-19 treatment. Accordingly, in this work, a structure-based virtual screening of 3.8 million ligand libraries was carried out. After rigorous filtering, docking, and post screening assessments, 78 compounds were selected for biological evaluation, 3 of which showed promising inhibition of the Mpro enzyme. The obtained hits (CB03, GR04, and GR20) had reasonable potencies with Ki values in the medium to high micromolar range. Interestingly, while our most potent hit, GR20, was suggested to act via a reversible covalent mechanism, GR04 was confirmed as a noncompetitive inhibitor that seems to be one of a kind when compared to the other allosteric inhibitors discovered so far. Moreover, all three compounds have small sizes (~300 Da) with interesting fittings in their relevant binding sites, and they possess lead-like characteristics that can introduce them as very attractive candidates for the future development of COVID-19 treatments.
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ISSN:1420-3049
1420-3049
DOI:10.3390/molecules27196710