Potential Inhibitors Targeting RNA-Dependent RNA Polymerase Activity (NSP12) of SARS-CoV-2

Abstract

A novel coronavirus (SARS-CoV-2) that is initially found to trigger human severe respiratory illness in Wuhan City of China in 2019, has killed 2,718 people in China by February 26, 2020, and which has been recognized as a public health emergency of international concern as well. And the virus has spread to more than 38 countries around the world. However, the drug has not yet been officially licensed or approved to treat SARS-Cov-2 infection. NSP12-NSP7-NSP8 complex of SARS-CoV-2, essential for viral replication and transcription, is generally regarded as a potential target to fight against the virus. According to the NSP12-NSP7-NSP8 complex (PDB ID: 6NUR) structure of SARS, two homologous models were established for virtual screening in the present study, namely NSP12-NSP7 interface model and NSP12-NSP8 interface model. Seven compounds (Saquinavir, Tipranavir, Lonafarnib, Tegobuvir, Olysio, Filibuvir, and Cepharanthine) were selected for binding free energy calculations based on virtual screening and docking scores. All seven compounds can combine well with NSP12-NSP7-NSP8 in the homologous model, providing drug candidates for the treatment and prevention of SARS-CoV-2.

Emerging SARS-CoV-2 mutation hot spots include a novel RNA-dependent-RNA polymerase variant

“…Some polymerase inhibitors [29,30] are currently being tested in clinical studies to target SARS-CoV-2 RdRp, including Favipiravir [17,19], Galidesivir [18], Remdesivir [19], Ribavirin [20], Penciclovir [31], Galidesivir [32] and Ponatinib [33]. Additionally, other drugs such as Simeprevir (FDA approved HCV protease inhibitor), as well as Filibuvir and Tegobuvir (both RdRp inhibitors) [22], are predicted to bind RdRp by molecular docking studies. In particular, a putative docking site was identified in a hydrophobic cleft very close to the mutated site 323 (P to L), corresponding to mutation 14408 identified in our study [22].…”

“…Additionally, other drugs such as Simeprevir (FDA approved HCV protease inhibitor), as well as Filibuvir and Tegobuvir (both RdRp inhibitors) [22], are predicted to bind RdRp by molecular docking studies. In particular, a putative docking site was identified in a hydrophobic cleft very close to the mutated site 323 (P to L), corresponding to mutation 14408 identified in our study [22]. Naturally occurring mutations in RdRp can potentially lead to drug-resistance phenomena, as already observed previously [19,34,35].…”

“…Interestingly, the docking site is not located in proximity to the catalytic domain of the RdRp [21]. In addition, other possible drugs such as Filibuvir, Cepharanthine, Simeprevir and Tegobuvir, are predicted to be potential inhibitors of RdRp [22]. Naturally occurring mutations in critical residues for drug efficacy can lead to drug resistance phenomena, with a significant loss in the binding affinity of these molecules to the RdRp.…”

Insights into SARS-CoV-2 genome, structure, evolution, pathogenesis and therapies: Structural genomics approach

“…As discussed earlier, the non-structural ORFs 1a and 1ab share the majority of nucleotide content of the viral genome. Replicase polyproteins are multifunctional proteins that perform various tasks, contributing to the viral pathogenesis [70]. However, the principal role of these proteins is to help in the transcription and replication of the viral RNA.…”

Targeting SARS-CoV-2 Nsp12/Nsp8 interaction interface with approved and investigational drugs: an in silico structure-based approach

“…Nsp12 is one of the conserved Nsp among coronaviruses (Gorbalenya et al, 2020). It has 'cupped right hand' structure with the subdomains including a finger domain, a palm domain, a thumb domain and a N-terminal extension domain with the total of 932 amino acids in length (Kirchdoerfer & Ward, 2019;Posthuma et al, 2017;Ruan et al, 2020;Sexton et al, 2016). The N-terminal extension domain has a nidovirus RdRp-associated nucleotidyltransferase (NiRAN) domain and an interface domain (Kirchdoerfer & Ward, 2019).…”