From SARS to MERS and SARS-CoV-2: Comparative Spike Protein Remodeling and Ligand-Binding Hot-Spots Revealed by Multiscale Simulations

The COVID-19 pandemic has prompted the scientific community to develop new weapons against the SARS-CoV-2 spike protein. The study of its mutations is important to understand how it interacts with human receptors and how to prevent a future pandemic. In this study, four mutations of the Omega variant, along with those from the SARS-CoV-1 and MERS variants, were analyzed in complex with the angiotensin-converting enzyme 2 (ACE2) receptor. In silico studies were carried out to demonstrate that these mutations affect the interaction with the compounds under investigation. The ligands studied are heterocyclic compounds previously considered as potential inhibitors. Our results show that these compounds interact well with the spike protein and provide insights into how mutations, especially in the RBD region, can lead to perturbations in ligand–protein interactions.