Zhai, T;
Zhang, F;
Haider, S;
Kraut, D;
Huang, Z;
(2021)
An Integrated Computational and Experimental Approach to Identifying Inhibitors for SARS-CoV-2 3CL Protease.
Frontiers in Molecular Biosciences
, 8
, Article 661424. 10.3389/fmolb.2021.661424.
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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 3CLproSARS– CoV– 1 and their corresponding IC50 data. The QSAR model assesses the physicochemical properties of identified compounds and estimates their inhibitory effects on 3CLproSARS– 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 IC50’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: | Article |
|---|---|
| Title: | An Integrated Computational and Experimental Approach to Identifying Inhibitors for SARS-CoV-2 3CL Protease |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.3389/fmolb.2021.661424 |
| Publisher version: | https://doi.org/10.3389/fmolb.2021.661424 |
| Language: | English |
| Additional information: | © 2021 Zhai, Zhang, Haider, Kraut and Huang. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
| Keywords: | SARS-CoV-2, 3CL protease inhibitors, docking, QSAR, IC50 |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > UCL School of Pharmacy UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > UCL School of Pharmacy > Pharma and Bio Chemistry |
| URI: | https://discovery-pp.ucl.ac.uk/id/eprint/10129440 |
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