Integrated computational approach towards identification of HSPG and ACE2 mimicking moieties for SARS-CoV-2 inhibition.

• Identification of HSPG and ACE2 mimicking moieties for competitive inhibition of SARS-CoV-2 cell entry. • Docking and molecular dynamics simulation studies revealed the binding characteristics of mimicking moieties with SARS-CoV-2. • Carboxymethyl benzyl amide sulfonate (CMBS) and polyanetholesulfonic acid (PAS) are the promising HSPG mimicking ligands. • Paenibacillus sp. B38-CAP and Bacillus subtilis BS-CAP carboxypeptidases are the potential ACE2-like enzymes. A key step to inhibit severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is to prevent the entry of the virus into the host cells. The receptor-binding domains (RBDs) of spike proteins of SARS-CoV and other human coronaviruses utilize heparan sulfate proteoglycans (HSPGs) as the primary receptors for their accumulation on the cell surface and then scan for binding to the main entry receptor angiotensin-converting enzyme 2 (ACE2). SARS-CoV and SARS-CoV-2 share structurally similar RBDs and therefore, it is possible that SARS-COV-2 primarily binds to HSPGs followed by binding to the ACE2 receptors. A promising strategy to inhibit virus infection is to circulate exogenous bioactive moieties structurally mimicking cellular HSPG and ACE2 which act as decoy receptors binding to SARS-CoV-2 and competitively inhibit virus entry to the host cells mediated by cellular-bound HSPG and ACE2. Using a molecular docking tool, we identified carboxymethyl benzyl amide sulfonate (CMBS) and polyanetholesulfonic acid (PAS) as the suitable HSPG mimicking ligands, and Paenibacillus sp. B38-derived carboxypeptidase (B38-CAP) and Bacillus subtilis -derived carboxypeptidase (BS-CAP) as the potential ACE2-like enzymes having a strong binding affinity to the spike proteins as that of cellular HSPG and ACE2. Further, the binding stability and compactness of these moieties with SARS-CoV-2 were analyzed through molecular dynamics (MD) simulations, and the results indicated that these moieties form well-stable complexes with the RBD of spike proteins. The identified moieties could be conjugated to the surfaces of non-toxic nanoparticles to provide multiple interactions to efficiently shield SARS-CoV-2, and inhibit viral entry to the host cells. [ABSTRACT FROM AUTHOR]