Molecular Dynamics and Inhibition of MERS CoV Papain-like Protease by Small Molecule Imidazole and Aminopurine Derivatives

Background: Middle East Respiratory Syndrome coronavirus (MERS CoV) is a newly emerged viral disease with a fatal outcome. Methods: During the search for new antiviral drugs, MERS CoV papain-like protease (Plpro) was identified as a possible target. In this work, MERS CoV Plpro was investigated by virtual screening, enzyme inhibition and molecular dynamics to find new inhibitors. After the virtual screening of a dataset of small molecules, 5 compounds were selected for inhibitory studies. Results: Purine and imidazole-pyridine derivatives were identified as MERS CoV Plpro inhibitors with Ki values of 73 and 68 μM, respectively. The binding of inhibitors showed marked changes in both the fingers subdomain and Ubl domain, with negligible changes in the catalytic domain. The binding of inhibitors was associated with the formation of favorable hydrogen bonds with the side chains of Plpro S1648 or Y1760. Conclusion: Further optimization of the present set can lead to more potent inhibitors through the design of small molecules with improved binding affinity.