Generate, Repurpose, Validate: A Receptor-Mediated Atom-by-Atom Drug Generation for SARS-Cov-2 Spike Protein and Similarity-Mapped Drug Repurposing for COVID-19 with Rigorous Free Energy Validation Using Well-Tempered Metadynamics

Finding a cure for Covid-19 is of immediate and paramount importance. In this study, we propose new and repurpose drugs to prevent SARS-Cov-2 (Covid-19) viral attack on human cells. Our study comprises three steps: generation of new molecules, structural similarity mapping to existing approved and investigational drugs, and validation of their binding strengths to the viral spike proteins based on rigorous all-atom well-tempered metadynamics free energy calculations. We show that some of our new molecules and some of the existing drugs bind more strongly than human ACE2 protein to the viral spike protein. Therefore, these drug molecules may have the potential to be repurposed as a preventive therapy for Covid-19, subject to further experimental verifications.