Discovery of raffinose sulfate as a potential SARS CoV-2 inhibitor via blocking its binding with angiotensin converting enzyme 2

Abstract

The present study aimed to characterize the possible binding sites on the SARS CoV-2 RBD-ACE2 complex and to highlight sulfated oligosaccharides as potential anti-SARS CoV-2 via inducing RBD-ACE2 complex destabilization and dissociation. By combining pharmacophore-based and structural-based virtual screening approaches we were able to discover raffinose sulfate (RS) as a potential antiviral sulfated oligosaccharide against two SARS CoV-2 variants (i.e., wild type and Omicron) (IC₅₀ = 4.45 ± 0.28 μM and 4.65 ± 0.32 μM, respectively). Upon MD simulation, RS was able to establish stable binding at the RBD-ACE2 interface inducing a rapid dissociation. Accordingly, and by using bio-layer interferometry (BLI) assays, RS was able to significantly weaken the affinity between RBD (of both variants) and ACE2. Additionally, we found that RS has a poor cellular permeability indicating that its interaction with the RBD-ACE2 complex may be the main mechanism by which it mediates its antiviral activity against SARS CoV-2. Despite its proposed interaction with the RBD-ACE2 complex, RS did not show any inhibitory activity against ACE2 catalytic activity. In light of these findings, the RS scaffold can be further developed into a novel anti-SARS CoV-2 drug with improved activity and tolerability in comparison with other sulfated polysaccharides e.g., heparin and heparan.

Keywords: Bio-layer interferometry; Molecular dynamics simulation; Pharmacophore; RBD-ACE2; SARS CoV-2; Sulfated oligosaccharides; Virtual screening.