Structure-based virtual screening and molecular docking of drugs against the SARS-CoV-2 spike protein-ACE2 receptor complex

The agent responsible for the COVID-19 pandemic was the newly discovered coronavirus SARS-CoV-2. A trimeric spike protein on the SARS-CoV-2 virion binds to the ACE2 receptor on host cells. In this study we performed a structure-based virtual screening and molecular docking of existing drugs against a high-resolution structure of the SARS-CoV-2 spike protein-ACE2 receptor complex. The 2.5-A crystal structure of the C-terminal domain of the SARS-CoV-2 spike protein (residues 319-541) in complex with human ACE2 (SARS-CoV-2-S-CTD/hACE2) (PDB ID: 6LZG) was used as the target for screening 4,374 FDA-approved drugs from the ZINC15 database using PyRx software. Molecular docking was performed using BIO VIA Discovery Studio Visualizer. The top twenty highest affinity drugs had binding energies of -7.0 to -8.8 kcal/mol. The highest affinity drug was the selective vasopressin V2-receptor antagonist Tolvaptan, for which molecular docking identified drug-amino acid residue interactions with ACE2. Other drugs displaying binding energies better than -8.0 kcal/mol were Nizoral, Amaryl, Accolate, Sorafenib, Glipizide and Azelastine. The predicted interactions of these highest affinity drugs with residues in ACE2 were at positions that could disrupt the spike protein-ACE2 complex, so these drugs have the potential to be repurposed as inhibitors of the SARS-CoV-2 virus.

Automated summary

This study used a structure-based virtual screening and molecular docking approach to identify existing drugs that may have the potential to inhibit the SARS-CoV-2 virus. The highest affinity drugs identified were Tolvaptan and Nizoral.