Computational Analysis of Synergistic Inhibitors of the Papain-Like Protease

Severe Acute Respiratory Syndrome (SARS) is a contagious viral disease that has a high mortality rate. The Papain-Like protease (PLpro) is an essential enzyme involved in viral replication, which makes it an attractive drug target. In previous studies, several inhibitors, comprising two different scaffolds, were discovered by High Throughput Screening (HTS) followed by Structure Activity Relationship (SAR) based lead optimization. In this study, in order to further optimize the compounds, a fragment screening was conducted in the presence of the previously discovered inhibitors and several compounds with synergistic activity in combination with the lead inhibitors were identified. Enzymatic profiling and computational techniques were applied to search the potential binding site for these fragments, which provided the foundation for proposing the next generation of compounds with novel structures for further synthesis and testing.