Paromomycin: A potential dual targeted drug effectively inhibits both spike (S1) and main protease of COVID-19

Abstract

With the increasing number of people suffering from coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), there is a dire need to look for effective remedies against this pandemic. Drug repurposing seems to be the solution for the current situation. Methods: In a quest to find a potential drug against this virus, 15 antimalarial drugs (including chloroquine) and 2413 US Food and Drug Administration-approved drugs were investigated for activity against both the protease and spike proteins of SARS-CoV-2 using an in silico approach. Molecular docking analysis followed by molecular dynamics simulation was performed to estimate the binding and stability of the complexes. Results: This study identified a single drugparomomycinwith activity against two targets of SARS-CoV-2, i.e., spike protein (S1) and protease domain. Paromomycin was found to have strong binding affinity for both targets of coronavirus. The results also showed that no antimalarial drug exhibited effective binding for either S1 or protease. Conclusions: This study found that paromomycin may be an effective dual targeting drug against coronavirus, as it binds not only to the protease domain of the virion, but also to the spike domain, with high stability. Furthermore, none of the antimalarial drugs showed strong binding affinity for either protease or the receptor binding domain (RBD).

Drug Repurposing for Candidate SARS-CoV-2 Main Protease Inhibitors by a Novel In Silico Method

“…Carbinoxamine showed in another docking study potential activity against SARS-CoV-2 M pro [ 33 ]. In the docking study of FDA approved drugs against protease and spike protein of COVID-19, paromomycin was found to have a strong binding affinity against both Spike and M pro of SARS-CoV-2 according to its glide score [ 34 ]. Phensuximide was found in molecular docking simulations of FDA-approved small compounds associated with protection against COVID-19, M pro [ 35 ].…”

The pulmonary route as a way to drug repositioning in COVID-19 therapy

“…The 17 articles selected by search criteria used different molecular targets: Mpro [ 8 , [14] , [15] , [16] , [17] , [18] , [19] ], RdRp [ [20] , [21] , [22] , [23] ], Spike protein [ 24 ], PLpro [ 25 ], NTD n-protein [ 26 ], EndoU or Nsp15 [ 27 ], TMPRSS2 [ 8 ], and RBD [ 15 ]. An amount of 12 of the 17 articles analyzed used programs to structure optimization/energy minimization and protonation, in addition to evaluating the chemical interactions observed between the molecular targets and ligands analyzed.…”

“…Elmezayen and coworkers [ 8 ] evaluated interactions between these residues and the ligands analyzed. The work of Tariq and coworkers [ 15 ] had RBD as one of the targets and interaction with 2 of the 5 amino acid residues of the active site already described has been reported (Gly496 and Try505), showing no interactions of the ligands analyzed with the Ans487, Glu37, Arg393 residues [ 35 , 36 ].…”

“…Likewise, the enzyme EndoU performs biological function in its hexameric form [ 38 ], however Chandra and coworkers [ 27 ] used its dimeric form (PDBid: 6W01) to perform the simulations. Tariq and coworkers [ 15 ] uses RBD as a molecular target in monomeric form, its biologically active form [ 39 ] (PDBid: 6Y84).…”

“…Its ability to reduce the inflammatory processes associated with cystic fibrosis and chronic lung diseases has been documented [ 43 , 44 ]. Regarding COVID-19, its ability to interact with the viral SARS-CoV-2 was evaluated in silico through molecular docking studies, showing that this drug could interact with specific sites of both main viral replication protease (Mpro) and S1 protein ( Table 1 ) [ 15 ].…”