Analysis of SARS-CoV-2 RNA-dependent RNA polymerase as a potential therapeutic drug target using a computational approach

Abstract

Background The Severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) outbreak originating in Wuhan, China, has raised global health concerns and the pandemic has now been reported on all inhabited continents. Hitherto, no antiviral drug is available to combat this viral outbreak. Methods Keeping in mind the urgency of the situation, the current study was designed to devise new strategies for drug discovery and/or repositioning against SARS-CoV-2. In the current study, RNA-dependent RNA polymerase (RdRp), which regulates viral replication, is proposed as a potential therapeutic target to inhibit viral infection. Results Evolutionary studies of whole-genome sequences of SARS-CoV-2 represent high similarity (> 90%) with other SARS viruses. Targeting the RdRp active sites, ASP760 and ASP761, by antiviral drugs could be a potential therapeutic option for inhibition of coronavirus RdRp, and thus viral replication. Target-based virtual screening and molecular docking results show that the antiviral Galidesivir and its structurally similar compounds have shown promise against SARS-CoV-2. Conclusions The anti-polymerase drugs predicted here—CID123624208 and CID11687749—may be considered for in vitro and in vivo clinical trials.

Promising terpenes as SARS-CoV-2 spike receptor-binding domain (RBD) attachment inhibitors to the human ACE2 receptor: Integrated computational approach

“…In this regard, the computational methods are scientifically sound to design extremely specific inhibitor for viral proteins, as an antiviral drug development/discovery. Recently, structural modeling has predicted a few drugs against SARS-CoV-2 proteins along with many other antiviral drugs [ 2 , 64 , 65 , 67 ].…”

A review on possible mechanistic insights of Nitazoxanide for repurposing in COVID-19

“…Recent molecular docking studies identified nitazoxanide amongst 10 most effective antipolymerase compounds with a docking score -9.76 indicating good binding affinity. Although the score was lower when compared with remdesivir (-14.06), galidesivir (-12.53), ribavirin (-11.88) and sofosbuvir (-11.13) it was comparable to nafamostat (-9.76), interferon (-9.62) and favipiravir (-9.36) ( Aftab et al, 2020 ) proposing great promise. Helicase (nsp13) promotes the separation of double stranded RNA to single stranded RNA mediated through nucleotide triphosphate (NTP) hydrolysis-dependent manner (NTPase) ( Shu et al, 2020 ).…”

“…Nitazoxanide not only exhibits the potential to inhibit all these major enzymes, but can also induce autophagy to disrupt protective environment of autophagosomes ( Lam et al, 2012 ; Senkowski et al, 2015 ; Shou et al, 2020 ). Among the enzymes RdRp plays major role in replication of genomic viral RNA, and RdRp of SARS-CoV-2 shares a 96% sequence identity with SARS-CoV ( Aftab et al, 2020 ; Gao et al, 2020 ). Recent molecular docking studies identified nitazoxanide amongst 10 most effective antipolymerase compounds with a docking score -9.76 indicating good binding affinity.…”

Codon usage pattern reveals SARS-CoV-2 as a monomorphic pathogen of hybrid origin with role of silent mutations in rapid evolutionary success

“…As these five viral proteins are common amongst betacoronaviruses (Woo et al, 2010), it will be useful in studying diverse coronaviruses from diverse hosts, i.e., humans, bat, pangolin, and dog. Presently, we have analyzed CUP of these five proteins in SARS coronavirus, which are considered important targets for vaccine and antiviral development for SARS-CoV-2 (Aftab et al, 2020;Du et al, 2009;Huang et al, 2020;Wu et al, 2020). CUP calculations should be based on highly redundant amino acids rather than amino acids having one or two codons.…”