Identifying promising druggable binding sites and their flexibility to target the receptor-binding domain of SARS-CoV-2 spike protein

• Published in: Computational and structural biotechnology journal Vol. 21; pp. 2339 - 2351
• Main Authors: Ghoula, M., Naceri, S., Sitruk, S., Flatters, D., Moroy, G., Camproux, A.C.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.01.2023; Published by Elsevier B.V. on behalf of Research Network of Computational and Structural Biotechnology; Elsevier
• Subjects: Binding site flexibility; biotechnology; COVID-19 variants; domain; Druggable binding sites; Hot spot residues; humans; Key-residues; molecular dynamics; Molecular dynamics simulation; mutation; peptidyl-dipeptidase A; Pocket tracking; prediction; SARS-CoV-2; Severe acute respiratory syndrome coronavirus 2; Spike protein; Structural flexibility; viruses; Pocket tracking; SARS-CoV-2; Spike protein; Binding site flexibility; Key-residues; COVID-19 variants; Structural flexibility; Molecular dynamics simulation; Druggable binding sites; Hot spot residues
• ISSN: 2001-0370; 2001-0370
• DOI: 10.1016/j.csbj.2023.03.029

The spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is crucial for viral infection. The interaction of its receptor-binding domain (RBD) with the human angiotensin-converting enzyme 2 (ACE2) protein is required for the virus to enter the host cell. We identified RBD binding sites to block its function with inhibitors by combining the protein structural flexibility with machine learning analysis. Molecular dynamics simulations were performed on unbound or ACE2-bound RBD conformations. Pockets estimation, tracking and druggability prediction were performed on a large sample of simulated RBD conformations. Recurrent druggable binding sites and their key residues were identified by clustering pockets based on their residue similarity. This protocol successfully identified three druggable sites and their key residues, aiming to target with inhibitors for preventing ACE2 interaction. One site features key residues for direct ACE2 interaction, highlighted using energetic computations, but can be affected by several mutations of the variants of concern. Two highly druggable sites, located between the spike protein monomers interface are promising. One weakly impacted by only one Omicron mutation, could contribute to stabilizing the spike protein in its closed state. The other, currently not affected by mutations, could avoid the activation of the spike protein trimer. [Display omitted] •Three druggable and stable target sites have been identified on the SARS-CoV-2 Spike RBD protein.•Site 3 could be targeted to prevent the ACE2 protein from interacting, though it is subject to mutations.•Sites 1 and 2 are not or slightly affected by the variant mutations and can be targeted to block spike protein activation.