Nsp14-Nsp10 protein interaction blockade as a new strategy for anti-Coronavirus co-adjuvant therapy. A virtual screening for repurposing drugs.

GÓMEZ MC; SCHIERLOH P; GARCÍA M; WIEBKE L

Simposio; 5to Simposio Argentino de Jóvenes Investigadores en Bioinformática; 2020

RSG-Argentina

Coronaviruses causing life threatening pandemic infections show proofreading 3'-exonuclease activity encoded by the nsp14 enzyme. This unique feature among RNA viruses renders COVID-19 virtually insensitive to every oral nucleoside analogues (NA) antivirals (i.e: Ribavirin, Favipiravir, Penciclovir, etc.) requiring high doses of intravenous Remdesivir in order to achieve only moderate effects. Given that Nsp14 requires Nsp10 binding before recruitment to the replicase complex, we speculate that blockade nsp14-nsp10 interaction may pose an adjuvant effect for NA-based chemotherapies. Therefore we performed a molecular docking-based virtual screening over 2893 DrugBank-Approved, 3153 DrugBank-Investigational, 2414 in-trials and 440 harmless natural investigational compounds on nsp14-nsp10 interfase as target surface. By using a 𝛥Gbinding ≤ -10 Kcal/mol as threshold, we identified 56 candidates that later were scored using clinical (CL) and pharmacodynamic (FD) available data combined with the qualitative and quantitative inspection of ligand-receptor concacting atoms (VMD, LigPlus). Top-10 compounds were selected for in silico validation by Molecular Dynamic Simulations (MDS) using high dimensional trajectory analysis (i.e: PCA vs time). Finally, based on combined MDS-FD-CL criteria, the top-5 ligands were selected for in vitro testing that soon will be conducted under BSL-3 biosafety level using the A549-infection model in the presence of 0.2xCI50 Ribavirin. The final goal will be identify those candidate repurposing compounds that augment the Ribavirin anti-coronavirus effect in at least 5-folds for pre-clinical investigation.