Computational screening of potential drugs against COVID-19 disease: the Neuropilin-1 receptor as molecular target

Abstract

The transmembrane receptor Neuropilin-1 (NRP-1) was reported to serve as a host cell entry factor for the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causal agent of COVID-19 disease. Therefore, molecular compounds interfering with SARS-CoV-2 binding to NRP-1 seem to be potential candidates as new antiviral drugs. In this study, NRP-1 receptor was targeted using a library of 1167 compounds previously analyzed in COVID-19 related studies. The results show the effectiveness of Nafamostat, Y96, Selinexor, Ebastine and UGS, in binding to NRP-1 receptor, with docking scores lower than -8.2 kcal/mol. These molecules interact with NRP-1 receptor key residues, which makes them promising drugs to pursue further biological assays to explore their potential use in the treatment of COVID-19.

Neuropilin-1 in the pathogenesis of preeclampsia, HIV-1, and SARS-CoV-2 infection: A review

“…A novel study observed a significant reduction of cell infection following pre-incubation of SARS-CoV-2 pseudovirus with recombinant soluble extracellular b1b2 domain of NRP-1 ( Cantuti-Castelvetri et al, 2020 ). Several amino acid residues at the NRP-1 binding site (Y297, W301, N313, T316, P317, E319, D320, S346, E348, T349, K351, and Y353) have become a target of interest to block SARS-CoV-2 S1 interaction ( Klaewkla et al, 2021 ; Charoute et al, 2022 ). Two monoclonal antibodies and a known NRP-1 antagonist molecule, EG00229, exhibited a considerable decrease in SARS-CoV-2 infection in cell culture by disrupting the interaction between the spike protein and the b1 domain of NRP-1 through high specificity binding of the NRP-1 CendR motif ( Daly et al, 2020 ).…”

“…The computational screening of five compounds showing potential against COVID-19 namely, Nafamostat, 5-[(E)-(hydroxyimino)methyl]-2-methyl-N-[(1R)-1-(naphthalen-1-yl)ethyl] benzamide (Y96), Selinexor, Ebastine and N-(4-methoxypyridin-2-yl)-2-(naphthalen-2-yl) acetamide (UGS) reveal lower NRP-1 docking scores (> -8.2kcal/mol) and more active key residue interactions than EG00229 and EG01377 (-6.6 and -7.1 kcal/mol, respectively ( Charoute et al, 2022 ). A recent study by Katopodis et al, identified three miRNAs (miR-148a-3p, miR-152-3p and miR-148b-3p) that may effectively regulate both NRP-1 and a disintegrin and metalloproteinase 17 (ADAM17), a sheddase responsible for ACE 2 receptor cleavage to its soluble form for potential decoy of SARS-CoV-2 cell entry ( Mulangu et al, 2019 ; Katopodis et al, 2022 ).…”

Phenotype-driven identification of drug targets for post-COVID-19 anosmia

“…This drug is a small molecule previously approved for pancreatitis. The literature supporting its COVID-19 trial suggests it directly targets SARS-CoV-2, but it is also predicted to bind to NRP1 10 . With this mechanism, it offers the potential to prevent or reduce the severity of SARS-CoV-2 infection, and hence avoid anosmia as a secondary effect.…”

Selinexor and COVID-19: The Neglected Warden

“…Thus, NRP-1 could be a potential target for SARS-CoV-2 infection. It has been shown by in vivo and in vitro testing that SXR has the ability to block the NRP-1 receptor ( Charoute et al, 2022 ). Therefore, SXR can reduce the pathogenesis of SARS-CoV-2 infection independent of the ACE2 pathway.…”

“…Therefore, SXR can reduce the pathogenesis of SARS-CoV-2 infection independent of the ACE2 pathway. However, the effect of SXR on other proposed SARS-CoV-2 receptors has been suggested but not documented ( Charoute et al, 2022 ).…”