Structure-based Virtual Screening from Natural Products as Inhibitors of SARS-CoV-2 Spike Protein and ACE2 Receptor Binding and their Biological Evaluation In vitro.

BACKGROUND: In the last years, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused more than 760 million infections and 6.9 million deaths. Currently, remains a public health problem with limited pharmacological treatments. Among the virus drug targets, the SARS-CoV-2 spike protein attracts the development of new anti-SARS-CoV-2 agents. OBJECTIVE: The aim of this work was to identify new compounds derived from natural products (BIOFACQUIM and Selleckchem databases) as potential inhibitors of the spike receptor binding domain (RBD)-ACE2 binding complex. METHODS: Molecular docking, molecular dynamics simulations, and ADME-Tox analysis were performed to screen and select the potential inhibitors. ELISA-based enzyme assay was done to confirm our predictive model. RESULTS: Twenty compounds were identified as potential binders of RBD of the spike protein. In vitro assay showed compound B-8 caused 48% inhibition at 50 µM, and their binding pattern exhibited interactions via hydrogen bonds with the key amino acid residues present on the RBD. CONCLUSION: Compound B-8 can be used as a scaffold to develop new and more efficient antiviral drugs.

Ligand- and Structure-Based Virtual Screening Identifies New Inhibitors of the Interaction of the SARS-CoV-2 Spike Protein with the ACE2 Host Receptor.

The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is a fast-spreading viral pathogen and poses a serious threat to human health. New SARS-CoV-2 variants have been arising worldwide; therefore, is necessary to explore more therapeutic options. The interaction of the viral spike (S) protein with the angiotensin-converting enzyme 2 (ACE2) host receptor is an attractive drug target to prevent the infection via the inhibition of virus cell entry. In this study, Ligand- and Structure-Based Virtual Screening (LBVS and SBVS) was performed to propose potential inhibitors capable of blocking the S receptor-binding domain (RBD) and ACE2 interaction. The best five lead compounds were confirmed as inhibitors through ELISA-based enzyme assays. The docking studies and molecular dynamic (MD) simulations of the selected compounds maintained the molecular interaction and stability (RMSD fluctuations less than 5 Å) with key residues of the S protein. The compounds DRI-1, DRI-2, DRI-3, DRI-4, and DRI-5 efficiently block the interaction between the SARS-CoV-2 spike protein and receptor ACE2 (from 69.90 to 99.65% of inhibition) at 50 µM. The most potent inhibitors were DRI-2 (IC50 = 8.8 µM) and DRI-3 (IC50 = 2.1 µM) and have an acceptable profile of cytotoxicity (CC50 > 90 µM). Therefore, these compounds could be good candidates for further SARS-CoV-2 preclinical experiments.