Identification of a New Drug Binding Site in the RNA-Dependent-RNA-Polymerase (RdRp) Domain

Abstract

We hypothesize that in silico structural biology approaches can discover novel drug binding sites for RNA-dependent-RNA-polymerases (RdRp) of positive sense single-strand RNA (ss(+)RNA) virus species. RdRps have a structurally conserved active site with seven motifs (A to G), despite low sequence similarity. We refined this architecture further to describe a conserved structural domain consisting of motifs A, B, C and F. These motifs were used to realign 24 RdRp structures in an innovative manner to search for novel drug binding sites. The aligned motifs from the enzymes were then docked with 833 FDA-approved drugs (Set 1) and 85 FDA-approved antivirals (Set 2) using the Molecular Operating Environment (MOE) docking 2020.09 software. Sirolimus (rapamycin), an immunosuppressant that targets the mammalian mTOR pathway, was one of the top ten drugs for all 24 RdRp proteins. The sirolimus docking site was in the nucleotide triphosphate entry tunnel between motifs A and F but distinct from the active site in motif C. This original finding supports our hypothesis that structural biology approaches based on RdRp motifs that are conserved across evolution can define new drug binding locations and infer potential broad-spectrum inhibitors for SARS-CoV-2 and other ss(+)RNA viruses.

An Exploration of the Inhibitory Mechanism of Rationally Screened Benzofuran-1,3,4-Oxadiazoles and-1,2,4-Triazoles as Inhibitors of NS5B RdRp Hepatitis C Virus through Pharmacoinformatic Approaches

“…ChemDraw Professional was used to prepare the ligands' structures, and then these ligands' structures in (.mol) format were imported into MOE, where the partial charges were incorporated into it, and the compounds' energies were minimized using the MMFF94x-ff. The protein structures were loaded and 3D protonated in MOE, and the site-finder function was then used to determine the allosteric pocket of the HCV NS5B enzyme [37]. The DOCK module of MOE software and the triangle matcher approach, along with the London-dG scoring algorithms, were selected to estimate the binding affinity of these compounds against the HCV NS5B enzyme.…”