In Silico and In Vitro Identification of New Eugenol Derivatives as Inhibitors of the Spike SARS ‐ CoV ‐2 Protein Interaction With the ACE2 Host Receptor

Coronavirus Disease‐2019 (COVID‐19) caused by SARS‐CoV‐2 remains a serious health concern worldwide. Inhibitors of the protein–protein interaction (iPPI) between the SARS‐CoV‐2 spike protein (S) and human Angiotensin‐Converting Enzyme‐2 (ACE2) are promising as potential antiviral agents. This study aimed to identify and evaluate novel compounds as inhibitors of the S receptor‐binding domain (RBD) and ACE2 interaction through Eugenol‐ and Structure‐Based virtual screening approaches. The hit compounds were corroborated as protein–protein interaction inhibitors using an ELISA‐based enzyme assay. Molecular docking and molecular dynamics (MD) studies of the selected compounds showed that they maintained a molecular interaction and stability (RMSD fluctuations less than 4 Å) with essential residues of the S protein. The best compound, Eu‐1 (IC 50 = 16 μM), prevented the interaction between the S protein and ACE2 receptor efficiently with an 83.7% inhibition at 50 μM. In addition, Eu‐1 had an adequate value of cytotoxicity (CC 50 > 200 μM). Therefore, Eu‐1 is a candidate compound for further SARS‐CoV‐2 preclinical experiments.