Virtual Screening of Inhibitors Against Spike Glycoprotein of SARS-CoV-2: A Drug Repurposing Approach

Abstract

The novel coronavirus (SARS-CoV-2) is a human pathogen recently emerged in China, causing a global pandemic of severe respiratory illness (COVID19). SARS-CoV-2 makes entry into human cells through its spike (S) protein that binds to cell surface receptors. Widespread of SARS-CoV-2 has been attributed to high affinity of S protein to its receptor. A homology model of the receptor binding domain of SARS-CoV-2 S protein (RBD) was built. RBD- receptor docking and published molecular dynamics data were used to map the key RBD-receptor interaction hotspot (RBDhp) on the RBD. Primary virtual screening was carried out against RBDhp using more than 3300 compounds approved by U.S Food and Drug Administration (FDA) and other authorities for human use. Compounds that bind to hpRBD with a binding energy ≤ - 6.5 kcal/mol were subjected to secondary screening using a recently published cryo EM (2.9 Å) structure of RBD. A cardiac glycoside (dgitoxin), two anthracyclines (zorubicin and aclarubicin), a tetracycline derivative (rolitetracycline), a cephalosporin (cefoperazone) and a food dye (E-155) were predicted to be most potent inhibitors of RBD – receptor interaction. An anti-asthmatic drug (zafirlukast) and several other drugs (itrazol, fazadinium, troglitazone, gliquidone, Idarubicin, Oxacillin) were found to be high affinity binders that may have a potential to inhibit RBD – receptor interaction.

In Silico Drug Repurposing for SARS-CoV-2 Main Proteinase and Spike Proteins

“…Working with two different possible RBD binding sites represents an advantage as compared to other similar studies, where a single but larger binding site on the RBD was defined. 18 , 69 Indeed, as previously said, most of the currently available drugs are small molecules which are able to interact with a limited surface and only with a few residues. Therefore, selecting two binding sites corresponding to specific hot spot clusters makes the docking pose search more efficient, by limiting the search space.…”

Screening Anti-inflammatory, Anticoagulant, and Respiratory Agents for SARS-CoV-2 3CL^pro Inhibition from Chemical Fingerprints Through a Deep Learning Approach

“…In a molecular docking study, zafirlukast was identified to interact significantly with 3CL pro49 . According to other virtual screenings conducted from homology models of receptor binding domain, zafirlukast may have the potential to inhibit the binding of another SARS-CoV-2 protein, the spike glycoprotein, to the ACE-2 receptor, adding another potential mechanism of action of the drug against viral infection 50,51 . Another deep learning study using MACCS fingerprints as molecular representations predicted this drug to inhibit 3CL pro52 .…”

Newly developed diagnostic methods for SARS-CoV-2 detection

“…The assay stands on a simple colorimetric ELISA platform, which measures the binding between immobilized SARS-CoV-2 S protein RBD (receptor binding domain) and Human ACE2 protein [51]. The tests can be used in the screening of inhibitors in SARS-CoV-2 binding tests or drug development against spike glycoprotein of SARS-CoV-2 [52], and a potential to develop a screening kit for the SARS-CoV-2 main protein (M protein) exists [53].…”