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 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. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s11224-020-01665-y) contains supplementary material, which is available to authorized users.