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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) pro...

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Main Authors: Timoteo Delgado-Maldonado (Author), Alonzo González-González (Author), Adriana Moreno-Rodríguez (Author), Virgilio Bocanegra-García (Author), Ana Verónica Martinez-Vazquez (Author), Erick de Jesús de Luna-Santillana (Author), Gerard Pujadas (Author), Guadalupe Rojas-Verde (Author), Edgar E. Lara-Ramírez (Author), Gildardo Rivera (Author)
Format: Book
Published: MDPI AG, 2024-05-01T00:00:00Z.
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Summary: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 (IC<sub>50</sub> = 8.8 µM) and DRI-3 (IC<sub>50</sub> = 2.1 µM) and have an acceptable profile of cytotoxicity (CC<sub>50</sub> > 90 µM). Therefore, these compounds could be good candidates for further SARS-CoV-2 preclinical experiments.
Item Description:10.3390/pharmaceutics16050613
1999-4923

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