Comparison of Binding Site of Remdesivir and Its Metabolites with NSP12-NSP7-NSP8, and NSP3 of SARS CoV-2 Virus and Alternative Potential Drugs for COVID-19 Treatment

Abstract

Remdesivir was approved by the U.S.A. Food and Drug administration for emergency use to interfere with the replication of SARS CoV-2 virus (the agent that causes COVID-19) in adults and children hospitalized with severe disease. The crystal structure of the metabolite of remdesivir (Monophosphate of GS-441524) and NSP12-NSP8-NSP7 of SARS CoV-2 virus was recently reported. The crystal structures of ADP-Ribose or AMP and NSP3 of SARS CoV-2 virus were also released, recently. This study compared their binding sites and suggests the crystal structure of NSP3 of SARS CoV-2 virus as an alternative binding site of AMP or ADP-ribose to treat COVID-19. We virtually screened 682 FDA-approved compounds, and the top 10 compounds were selected by analysis of docking scores, (G-score, D-score, and Chemscore) and visual analysis using a structure-based docking approach of NSP3 of SARS CoV-2 virus. All immunization approaches are based on the SARS-CoV-2 virus spike protein. A recent study reported that the D614G mutation in the SARS-CoV-2 virus spike protein reduces S1 shedding and increases infectivity of SARS COV-2 virus. Therefore, if there is a severe change in the spike protein of a modified Coronavirus, all developed vaccines can lose their efficacy, necessitating the need for an alternative treatment method. The top 10 compounds (FDA-approved) in this study are selected based on NSP 3 binding site, and therefore are a potential viable treatment because they will show potential activity for all mutations in the SARS-CoV-2 virus spike protein.

Keywords: Non-structural protein 3 (NSP3) of SARS CoV-2 virus; Remdesivir; Virtual screening.

Fig. 1

Metabolism of remdesivir (prodrug) into GS-41524 (parent drug) [4]

Fig. 2

Structures of ATP, ADP, and AMP-like (size) compounds; (a) Adenosine-5′-triphosphate, (b) Adenosine-5′-diphosphate, (c) Adenosine monophosphate, (d) Adenosine-5-Diphosphoribose, (e) GS-704277, (f) Monophosphate of GS-441524, (g) Triphosphate of GS-441524, and (h) Diphosphate of GS-441524

Fig. 3

Analysis Molecular Surfaces AMP with crystal structure of NSP3 (PDB: 6W6Y) (a) Hydrogen Bond between NSP3 and AMP, (b) Molecular Electrical Potential Surfaces of AMP, and (c) Molecular Surface displayed by Cavity Depth for NSP3

Fig. 4

Analysis Molecular Surfaces ADP-ribose with crystal structure of NSP3 (PDB: 6WOJ) (a) Hydrogen Bond between NSP3 and ADP-ribose, (b) Molecular Electrical Potential Surfaces of ADP-ribose, and (c) Molecular Surface displayed by Cavity Depth for NSP3

Fig. 5

Analysis Molecular Surfaces AMP with crystal structure of NSP3 (PDB: 6W6Y) (a) Molecular Lipophilic Potential Surfaces of NSP3 and AMP, (b) Molecular Electrical Potential Surfaces of NSP3 and AMP

Fig. 6

Analysis Molecular Surfaces ADP-ribose with crystal structure of NSP3 (PDB: 6WOJ) (a) Molecular Lipophilic Potential Surfaces of NSP3 and ADP-ribose, (b) Molecular Electrical Potential Surfaces of NSP3 and ADP-ribose

Fig. 7

Superimposed NSP3 of SARS COV-2 with AMP and ADP-ribose (PDB: 6WOJ) (a) Molecular Surface by Cavity Depth for NSP3 with AMP (PDB: 6W6Y), (b) Superimposed NSP3 with AMP and ADP-ribose (PDB: 6W6Y, 6WOJ), (c) Molecular Surface by Cavity Depth for NSP3 with ADP-ribose (PDB: 6WOJ)

Fig. 8

Superimposed NSP12 of SARS COV-2 with Monophosphate of GS-441524; (a) Molecualr Surface of NSP12 (PDB: 7BV2), (b) Superimposed NSP12 (PDB: 7BV2, 6 M71), (c) Molecular Surface of NSP12 (PDB: 6 M71)

Fig. 9

(a) Superimposition, and (b) Sequence Alignment of NSP3 in SARS COV-2 (purple, PDBL 6WOJ) and SARS-CoV (orange, PDB: 2FAV) (Color figure online)

Fig. 10

Superimposition of the crystal structure of the metabolite of Remdesivir (PDB: 7BV2) in wild type (purple) and V557L (orange) with UTP (Uridine phosphate, green) (Color figure online)

Fig. 11

Docking poses in the cavity of NSP3 for top 10 compounds and Redesivir and its parent compound (GS-441524); (a) (top 1) Folic acid, (b) (top 2) Telmisartann, (c) (top 3) Methotrexate, (d) (top 4) Bosentan, (e) (top 5) Lapatinib, (f) (top 6) Gefitinib, (g) (top 7) Ketoconazole, (h) (top 8) Carvedilol, (i) (top 9) Glyburide, (j) (top 10) Avanafil, (k) (refernce) Remdesivir, and (l) (reference) GS-441524

Fig. 12

Docking poses in the cavity of NSP3 for top 9 compounds with active sites, generating H-bonds; (a) (top 1) Folic acid, (b) (top 2) Telmisartann, (c) (top 3) Methotrexate, (d) (top 4) Bosentan, (e) (top 5) Lapatinib, (f) (top 6) Gefitinib, (g) (top 7) Ketoconazole, (h) (top 8) Carvedilol, (i) (top 9) Glyburide

Fig. 13

Docking poses of Remdesivir and Folic Acid (top 1) with NSP3 of SARS COV-2; (a) H-bonds of NSP3 with Remdesivir (green) and Folic acid, (b) The cavity of NSP3 with Remdesivir (green) and Folic acid (Color figure online)