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 1 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.
【저자키워드】 COVID-19, docking, PLPro, Benchmarking, VS, DEKOIS 2.0, 【초록키워드】 coronavirus disease, SARS-CoV-2, coronavirus, pandemic, SARS-CoV, Virtual screening, database, binding site, Papain-like protease, X-ray, virus replication, small molecule, DrugBank, AutoDock, Ligand, Analysis, acute respiratory syndrome, residue, submission, manuscript, sequence identity, approach, homology model, ENhance, flexible, performed, caused, example, reported, generate, provide, introduced, comparable, docking tool, ligand-bound, peptide-like inhibitor, 【제목키워드】 SARS-CoV-2, drug, Supporting,