In silico structure modelling of SARS-CoV-2 Nsp13 helicase and Nsp14 and repurposing of FDA approved antiviral drugs as dual inhibitors

Abstract

The high mortality rate from the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections in humans and the lack of effective therapeutic regime for its treatment necessitates the identification of new antivirals. SARS-CoV-2 relies on non-structural proteins such as Nsp13 helicase and nsp14 which are the key components of the replication-transcription complex (RTC) to complete its infectious life cycle. Therefore, targeting these essential viral proteins with small molecules will most likely to halt the disease pathogenesis. The lack of experimental structures of these proteins deters the process of structure-based identification of their specific inhibitors. In the present study, the in silico models of SARS-CoV-2 nsp13 helicase and nsp14 protein were elucidated using a comparative homology modelling approach. These in silico model structures were validated using various parameters such as Ramachandran plot, Verify 3D score, ERRAT score, knowledge-based energy and Z-score. The in silico models were further used for virtual screening of the Food and Drug Administration (FDA) approved antiviral drugs. Simeprevir (SMV), Paritaprevir (PTV) and Grazoprevir (GZR) were the common leads identified which show higher binding affinity to both nsp13 helicase and nsp14 as compared to the control inhibitors and therefore, they might be potential dual-target inhibitors. The leads also establish a network of hydrogen bonds and hydrophobic interactions with the key residues lining the active site pockets. The present findings suggest that these FDA approved antiviral drugs can be subjected to repurposing against SARS-CoV-2 infection after verifying the in silico results through in vitro and in vivo studies.

Screening of potent drug inhibitors against SARS-CoV-2 RNA polymerase: an in silico approach

“…Compound 3a (Paritaprevir) is an antiviral drug used to treat chronic hepatitis C as part of the combination treatment (Wilkins et al 2015 ). This drug was also studied against nsp 15 protein by Khan et al ( 2020 ) and against nsp13 helicase and nsp14 of SARS-CoV-2 by Gurung ( 2020 ). The compound 3a showed the highest binding affinity (− 10.2 kcal/mol) and had hydrogen bonds with amino acids Arg553, Asp623, Thr687, Ser759; whereas hydrophobic interaction with Tyr455, Tyr619, Pro620, Lys621, Cys622, Ser681, Ser682, Ala688, Asn691 and Asp760 residues (Fig.…”

Hepatitis C Virus Protease Inhibitors Show Differential Efficacy and Interactions with Remdesivir for Treatment of SARS-CoV-2in Vitro

“…It should be noted that simeprevir was also described to impact cellular innate immune responses 61 and Spike, were suggested for paritaprevir, grazoprevir and simeprevir by modelling studies. 53,67,[78][79][80][81][82] Future detailed molecular studies are required to fully define the viral targets of different HCV preprint (which was not certified by peer review) is the author/funder. All rights reserved.…”

“…It should be noted that simeprevir was also described to impact cellular innate immune responses 61 and that alternative viral targets, including nsp3 (papain like protease domain), nsp12 (polymerase), nsp13 (helicase), nsp14 (exonuclease and methyltransferase), nsp15 (endoribonuclease), nsp16 (2’-o-ribose methyltransferase), as well as structural proteins N (capsid) and Spike, were suggested for paritaprevir, grazoprevir and simeprevir by modelling studies. 53,67,78–82 Future detailed molecular studies are required to fully define the viral targets of different HCV PI.…”

Recent progress of antiviral therapy for coronavirus disease 2019

“…In another study, the researchers screened a large database of more than 606 million compounds and discovered twelve novel inhibitors of SARS-CoV-2 3-chymotrypsin-like protease, including natural substances like rhamnetin, and existing protease inhibitors such as nelfinavir and so on ( Fischer et al, 2020 ). Another study used virtual screening technology in silico models to find molecules that may inhibit both SARS-CoV-2 Nsp13 helicase and Nsp14 proteins from the FDA-approved drug library ( Gurung, 2020 ).…”