Supporting SARS-CoV-2 Papain-Like Protease Drug Discovery: In silico Methods and Benchmarking

The coronavirus disease 19 (COVID-19) is a rapidly growing pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Its papain-like protease (SARS-CoV-2 PLpro) is a crucial target to halt virus replication. SARS-CoV PLpro and SARS-CoV-2 PLpro share an 82.9% sequence identity and a 100% sequence identity for the binding site reported to accommodate small molecules in SARS-CoV. The flexible key binding site residues Tyr269 and Gln270 for small-molecule recognition in SARS-CoV PLpro exist also in SARS-CoV-2 PLpro. This inspired us to use the reported small-molecule binders to SARS-CoV PLpro to generate a high-quality DEKOIS 2.0 benchmark set. Accordingly, we used them in a cross-benchmarking study against SARS-CoV-2 PLpro. As there is no SARS-CoV-2 PLpro structure complexed with a small-molecule ligand publicly available at the time of manuscript submission, we built a homology model based on the ligand-bound SARS-CoV structure for benchmarking and docking purposes. Three publicly available docking tools FRED, AutoDock Vina, and PLANTS were benchmarked. All showed better-than-random performances, with FRED performing best against the built model. Detailed performance analysis via pROC-Chemotype plots showed a strong enrichment of the most potent bioactives in the early docking ranks. Cross-benchmarking against the X-ray structure complexed with a peptide-like inhibitor confirmed that FRED is the best-performing tool. Furthermore, we performed cross-benchmarking against the newly introduced X-ray structure complexed with a small-molecule ligand. Interestingly, its benchmarking profile and chemotype enrichment were comparable to the built model. Accordingly, we used FRED in a prospective virtual screen of the DrugBank database. In conclusion, this study provides an example of how to harness a custom-made DEKOIS 2.0 benchmark set as an approach to enhance the virtual screening success rate against a vital target of the rapidly emerging pandemic.