Virtual and biochemical screening to identify the inhibitors of binding between SARS-CoV-2 spike protein and human angiotensin-converting enzyme 2

Severe acute respiratory syndrome coronavirus (SARS-CoV-2) appeared as a new viral pathogen and caused the COVID-19 pandemic worldwide. Since the antiviral medicines effective for the treatment of COVID-19 are rare, it is necessary to identify the new candidate molecules for chemotherapy. The glycosylated Spike protein (S-protein) of SARS-CoV-2 plays a critical role in entering into the host cell through a direct interaction with human angiotensin-converting enzyme 2 (ACE2). For this reason, S-protein has served as one of the most effective therapeutic targets for discovering the antiviral medicines for COVID-19. In this work, we report the new small-molecule inhibitors of the interaction between the S-protein of SARS-CoV-2 and human ACE2, which were discovered through the structure-based virtual screening and in vitro biochemical binding assays. As a consequence of combining the computational and experimental validations, three novel inhibitors against the binding of S-protein and ACE2 were found with the associated IC(50) values ranging from 50 to 100 μM. Although the biochemical potencies are moderate, the newly found inhibitors are worth being considered for further investigation by structure-activity relationship analysis to maximize the antiviral activity because of the low molecular weights and good physicochemical properties as a drug candidate. The interaction patterns of the new inhibitors in the ACE2-binding region of S-protein are addressed in detail.