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. 2020 Jun 25;13(6):132.
doi: 10.3390/ph13060132.

Preliminary Virtual Screening Studies to Identify GRP78 Inhibitors Which May Interfere with SARS-CoV-2 Infection

Andreia Palmeira  1   2 , Emília Sousa  1   2 , Aylin Köseler  3 , Ramazan Sabirli  4 , Tarık Gören  5 , İbrahim Türkçüer  5 , Özgür Kurt  6 , Madalena M Pinto  1   2 , M Helena Vasconcelos  7   8   9
Affiliations

Preliminary Virtual Screening Studies to Identify GRP78 Inhibitors Which May Interfere with SARS-CoV-2 Infection

Andreia Palmeira et al. Pharmaceuticals (Basel). .

Erratum in

Abstract

SARS-CoV-2 Spike protein was predicted by molecular docking to bind the host cell surface GRP78, which was suggested as a putative good molecular target to inhibit Covid-19. We aimed to confirm that GRP78 gene expression was increased in blood of SARS-CoV-2 (+) versus SARS-CoV-2 (-) pneumonia patients. In addition, we aimed to identify drugs that could be repurposed to inhibit GRP78, thus with potential anti-SARS-CoV-2 activity. Gene expression studies were performed in 10 SARS-CoV-2 (-) and 24 SARS-CoV-2 (+) pneumonia patients. A structure-based virtual screen was performed with 10,761 small molecules retrieved from DrugBank, using the GRP78 nucleotide binding domain and substrate binding domain as molecular targets. Results indicated that GRP78 mRNA levels were approximately four times higher in the blood of SARS-CoV-2 (+) versus SARS-CoV-2 (-) pneumonia patients, further suggesting that GRP78 might be a good molecular target to treat Covid-19. In addition, a total of 409 compounds were identified with potential as GRP78 inhibitors. In conclusion, we found preliminary evidence that further proposes GRP78 as a possible molecular target to treat Covid-19 and that many clinically approved drugs bind GRP78 as an off-target effect. We suggest that further work should be urgently carried out to confirm if GRP78 is indeed a good molecular target and if some of those drugs have potential to be repurposed for SARS-CoV-2 antiviral activity.

Keywords: Covid-19; GRP78; SARS-CoV-2; antiviral; gene expression; repurposed drugs; virtual screening.

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Conflict of interest statement

The authors declare no conflict of interest. M.H.V. is member of the research team of a project financed by Celgene. M.H.V. is member of the team of a grant co-financed by AMGEN. These companies had no role in the decision to publish this manuscript, nor were they involved in the writing of this manuscript.

Figures

Figure 1
Figure 1
Docking studies on GRP78 nucleotide binding domain (NBD). (A) Three-dimensional (3D) surface structure of GRP78 (pdb code 5e84) showing its nucleotide-binding domains (yellow circle). (B) Crystallographic ATP, and (C) known drug Ponatinib, in 3D representation (left image) and respective two-dimensional (2D) interaction scheme (right image). The polar and non-polar amino-acids are shown in pink and green circles; hydrogen bonding is indicated by dotted arrows; with dotted lines represent arene-hydrogen interactions; proximity contour are dotted lines surrounding the ligand, indicating the shape of the binding site and available space to the more outward-facing parts of the ligand; blue shadows in some amino acids indicate the receptor exposure differences by the size and intensity of the quoits disks. The directions of the shadows indicate the directions of the amino acids toward the ligands. The blue clouds around the ligand atoms indicate the solvent exposure.
Figure 2
Figure 2
Docking studies on GRP78 SBD. (A) 3D surface structure of GRP78 (pdb code 5e84) (grey surface) bound to SARS-CoV-2 (red transparent surface); the C480–C488 section of the whole SARS-CoV-2 spike (pdb code 6m0j) was aligned with the docked C480–C488 in order to allow an easier visualization of the position of the spike towards the GRP78 target. Known peptide Zilucoplan is shown in sticks for exemplification. (B) SARS-CoV-2 region IV, and (C) known drug Zilucoplan bound to GRP78 SBD in 3D representation (left image, with arrows representing the direction of the peptidic strand from the linear—I, II, III—to the macrocyclic segment—IV) and respective 2D interaction scheme (right image). The polar and non-polar amino-acids are shown in pink and green circles; hydrogen bonding is indicated by dotted arrows; proximity contour are dotted lines surrounding the ligand, indicating the shape of the binding site and available space to the more outward-facing parts of the ligand; blue shadows in some amino acids indicate the receptor exposure differences by the size and intensity of the quoits disks. The directions of the shadows indicate the directions of the amino acids toward the ligands. The blue clouds around the ligand atoms indicate the solvent exposure.
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