Characterization of the NiRAN domain from RNA-dependent RNA polymerase provides insights into a potential therapeutic target against SARS-CoV-2

Abstract

Apart from the canonical fingers, palm and thumb domains, the RNA dependent RNA polymerases (RdRp) from the viral order Nidovirales possess two additional domains. Of these, the function of the Nidovirus RdRp associated nucleotidyl transferase domain (NiRAN) remains unanswered. The elucidation of the 3D structure of RdRp from the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), provided the first ever insights into the domain organisation and possible functional characteristics of the NiRAN domain. Using in silico tools, we predict that the NiRAN domain assumes a kinase or phosphotransferase like fold and binds nucleoside triphosphates at its proposed active site. Additionally, using molecular docking we have predicted the binding of three widely used kinase inhibitors and five well characterized anti-microbial compounds at the NiRAN domain active site along with their drug-likeliness. For the first time ever, using basic biochemical tools, this study shows the presence of a kinase like activity exhibited by the SARS-CoV-2 RdRp. Interestingly, a well-known kinase inhibitor- Sorafenib showed a significant inhibition and dampened viral load in SARS-CoV-2 infected cells. In line with the current global COVID-19 pandemic urgency and the emergence of newer strains with significantly higher infectivity, this study provides a new anti-SARS-CoV-2 drug target and potential lead compounds for drug repurposing against SARS-CoV-2.

Molecular docking studies of phytochemicals from Terminalia chebula for identification of potential multi-target inhibitors of SARS-CoV-2 proteins

“…The interface domain serves as a connector between NiRAN and polymerase domain. This domain is also known to work as binding partner for Nsp8 protein of the poly-protein complex ( Dwivedy et al, 2021 ). Binding of these molecules to this domain may hinder the formation of polyprotein complex and also disturb the connectivity between the functional domains.…”

Identification of probable inhibitors for the DNA polymerase of the Monkeypox virus through the virtual screening approach

“…Lipinski's Rule of Five is not the only primary criteria for drug candidates. Other physicochemical properties like ADME help to understand human metabolite's behavior against the drug candidate [45] , [65] . The safety and efficacy of molecules play a significant role in developing a small molecule as a better drug candidate.…”

Intragenomic rearrangements involving 5′-untranslated region segments in SARS-CoV-2, other betacoronaviruses, and alphacoronaviruses

“…The 5′-UTR sequence at the proximal site in the nsp12 NiRAN domain overlaps with one of the interface regions with nsp9 but does not affect key interface residues or alter the charge distribution of amino acid side chains in the overlap region. The nsp12 NiRAN domain also exhibits a kinase/phosphotransferase like activity [ 67 ], is involved in protein-primed initiation of RNA synthesis [ 68 ] and catalyzes the formation of the cap core structure (GpppA; contact regions with GDP [ 66 ] indicated with blue boxes and key residues therein in ochre in Fig. 4 A) [ 69 ].…”