Discovery of small molecule PLpro inhibitor against COVID-19 using structure-based virtual screening, molecular dynamics simulation, and molecular mechanics/Generalized Born surface area (MM/GBSA) calculation

COVID-19 is spreading in a global pandemic that is endangering human life and health. Therefore, there is an urgent need to target COVID-19 to find effective treatments for this emerging acute respiratory infection. Viral Papain-Like cysteine protease (PLpro), similar to papain and the cysteine deub...

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Bibliographic Details
Published in:Structural chemistry 2021-04, Vol.32 (2), p.879-886
Main Authors: Pang, Jie, Gao, Shan, Sun, Zengxian, Yang, Guangsheng
Format: Article
Language:English
Subjects:
Chemical bonds
Chemistry
Chemistry and Materials Science
Cluster analysis
Clustering
Computer Applications in Chemistry
Coronaviruses
COVID-19
Cysteine
Disease transmission
Enzymes
Free energy
Hydrogen bonds
Hydrophobicity
Inhibitors
Mathematical analysis
Mechanics (physics)
Molecular docking
Molecular dynamics
Molecular structure
Original Research
Papain
Physical Chemistry
Scaffolds
Screening
Simulation
Surface area
Theoretical and Computational Chemistry
Viral diseases
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Summary:COVID-19 is spreading in a global pandemic that is endangering human life and health. Therefore, there is an urgent need to target COVID-19 to find effective treatments for this emerging acute respiratory infection. Viral Papain-Like cysteine protease (PLpro), similar to papain and the cysteine deubiquitinase enzyme, has been a popular target for coronavirus inhibitors, as an indispensable enzyme in the process of coronavirus replication and infection of the host. Combined structure-based virtual screening, molecular dynamics (MD) simulation, and molecular mechanics/Generalized Born surface area (MM/GBSA) free energy calculation approaches were utilized for identification of PLpro inhibitors. Four compounds (F403_0159, F112_0109, G805_0497, D754_0006) with diverse chemical scaffolds were retrieved as hits based on docking score and clustering analysis. Molecular dynamics simulations indicated that the contribution of van der Waals interaction dominated the binding free energies of these compounds, which may be attributed to the hydrophobicity of active site of PLpro from COVID-19. Moreover, all four compounds formed conservative hydrogen bonds with the residues Asp164, Gln269, and Tyr273. We hoped that these four compounds might represent the promising chemical scaffolds for further development of novel PLpro inhibitors against COVID-19.
ISSN:1040-0400
1572-9001
DOI:10.1007/s11224-020-01665-y