In:
Frontiers in Molecular Biosciences, Frontiers Media SA, Vol. 8 ( 2021-5-17)
Abstract:
The newly evolved SARS-CoV-2 has caused the COVID-19 pandemic, and the SARS-CoV-2 main protease 3CLpro is essential for the rapid replication of the virus. Inhibiting this protease may open an alternative avenue toward therapeutic intervention. In this work, a computational docking approach was developed to identify potential small-molecule inhibitors for SARS-CoV-2 3CLpro. Totally 288 potential hits were identified from a half-million bioactive chemicals via a protein-ligand docking protocol. To further evaluate the docking results, a quantitative structure activity relationship (QSAR) model of 3CLpro inhibitors was developed based on existing small molecule inhibitors of the 3CLpro SARS– CoV– 1 and their corresponding IC 50 data. The QSAR model assesses the physicochemical properties of identified compounds and estimates their inhibitory effects on 3CLpro SARS– CoV– 2 . Seventy-one potential inhibitors of 3CLpro were selected through these computational approaches and further evaluated via an enzyme activity assay. The results show that two chemicals, i.e., 5-((1-([1,1′-biphenyl]-4-yl)-2,5-dimethyl-1H-pyrrol-3-yl)methylene)pyrimidine-2,4,6(1H,3H,5H)-trione and N-(4-((3-(4-chlorophenylsulfonamido)quinoxalin-2-yl)amino)phenyl)acetamide, effectively inhibited 3CLpro SARS-CoV-2 with IC 50 ’s of 19 ± 3 μM and 38 ± 3 μM, respectively. The compounds contain two basic structures, pyrimidinetrione and quinoxaline, which were newly found in 3CLpro inhibitor structures and are of high interest for lead optimization. The findings from this work, such as 3CLpro inhibitor candidates and the QSAR model, will be helpful to accelerate the discovery of inhibitors for related coronaviruses that may carry proteases with similar structures to SARS-CoV-2 3CLpro.
Type of Medium:
Online Resource
ISSN:
2296-889X
DOI:
10.3389/fmolb.2021.661424
DOI:
10.3389/fmolb.2021.661424.s001
DOI:
10.3389/fmolb.2021.661424.s002
DOI:
10.3389/fmolb.2021.661424.s003
DOI:
10.3389/fmolb.2021.661424.s004
Language:
Unknown
Publisher:
Frontiers Media SA
Publication Date:
2021
detail.hit.zdb_id:
2814330-9
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