Virtual Screening and Inhibition of Middle East Respiratory Syndrome Coronavirus Replication by Targeting Papain-like Protease
Mahmoud Kandeel, Byoung Kwon Park, Mohamed A. Morsy, Katharigatta N. Venugopala, Kentaro Oh‐hashi, Mohammed Al‐Nazawi, Hyung‐Joo Kwon
Abstract
Infection by the emerging, potentially zoonotic Middle East Respiratory Syndrome Coronavirus (MERS-CoV) presents a severe health hazard to humans and is often fatal. Given the lack of particular medicines against MERS-CoV, drug discovery studies are needed to bridge this knowledge gap. In this study, we introduce virtual screening-guided identification of MERS-CoV Papainlike Protease (PL pro )-binding drugs. After a two-step virtual screening method, enzyme assays and antiviral testing with a MERSCoV plaque reduction assay were used to further investigate the five compounds with the highest computational score. The top five screened compounds showed a 10.2-40% decrease in MERS-CoV PL pro activity. The top two compounds showed promising inhibition of MERS-CoV replication, reducing virus plaque formation by 30.6% and 24%. Compounds 1 and 4 in this study can be further modified to target binding with MERS-CoV PL pro active triad residues. Furthermore, the compounds produced stable interaction with the protein and protein conformation. With their reported inhibition of MERS-CoV enzyme and virus replication, supported by favorable absorption, distribution, metabolism, and excretion and toxicity profiles, the two reported benzimidazole and piperazine derivatives could be considered lead compounds against MERS-CoV.