Targeting SARS-CoV-2 endoribonuclease: a structure-based virtual screening supported by in vitro analysis

Abstract

Researchers are focused on discovering compounds that can interfere with the COVID-19 life cycle. One of the important non-structural proteins is endoribonuclease since it is responsible for processing viral RNA to evade detection of the host defense system. This work investigates a hierarchical structure-based virtual screening approach targeting NSP15. Different filtering approaches to predict the interactions of the compounds have been included in this study. Using a deep learning technique, we screened 823,821 compounds from five different databases (ZINC15, NCI, Drug Bank, Maybridge, and NCI Diversity set III). Subsequently, two docking protocols (extra precision and induced fit) were used to assess the binding affinity of the compounds, followed by molecular dynamic simulation supported by the MM-GBSA free binding energy. Interestingly, one compound (ZINC000104379474) from the ZINC15 database has been found to have a good binding affinity of − 7.68 kcal/Mol. The VERO-E6 cell line was used to investigate its therapeutic effect in vitro. Half-maximal cytotoxic concentration and Inhibitory concentration 50 were determined to be 0.9 mg/ml and 0.01 mg/ml, respectively; therefore, the selectivity index is 90. In conclusion, ZINC000104379474 was shown to be a good hit for targeting the virus that needs further investigations in vivo to be a drug candidate.

Inhibition of SARS–CoV–2 NSP–15 by Uridine–5′–Monophosphate Analogues Using QSAR Modelling, Molecular Dynamics Simulations, and Free Energy Landscape

“…It showed RMSD in the 0.2 nm to 0.3 nm which was stable and consistent. Similar RMSD trend was observed by a previous study for NSP15-ZINC000104379474 complex, which showed promising results against SARS-CoV-2( Ibrahim et al, 2022 ). RMSD values within this range represent a relatively stable structure, with minor fluctuations and deviations from the starting conformation.…”

“…The apo state of the protein (blue line) without the ligand remains relatively consistent but slightly more compact compared to the other complexes. Similar results were observed by the prior investigated protein–ligand complex (NSP15-ZINC000104379474 complex) ( Ibrahim et al, 2022 ). The protein–ligand complexes exhibit varying degrees of stability, with the control appearing the most stable in terms of Rg.…”

“…The root–mean–square deviation (RMSD), root–mean–square fluctuation (RMSF), and hydrogen bond formation between the ligands and the protein were the main topics of a thorough examination of molecular dynamics simulations. The analyses of RMSD, RMSF, and Radius of Gyration (Rg) plots in this study exhibited patterns consistent with a previous investigation targeting Nsp15, as conducted by Ibrahim et al in 2022 ( Ibrahim et al, 2022 ). During the 100 ns molecular dynamics (MD) simulation, both compounds 53309102 and 57398422 demonstrated robust and sustained binding interactions with the protein, a phenomenon congruent with the RMSD plot.…”

“…However, 57,398,422 showed high fluctuations (RMSF > 0.3 nm) for the 18 residues. The study showed similar RMSF trend to that of a prior study targeting NSP15 ( Ibrahim et al, 2022 ). These residues exhibited significant fluctuations during the simulation could be the cause of ligand binding which induced conformational changes and increased flexibility in the binding site or nearby regions of the protein.…”

Investigating the Structure-Activity Relationship of Laulimalides Marine Macrolides as Promising Inhibitors for SARS-CoV-2 Main Protease (Mpro)

“…These in-silico methods successfully predicted novel potential inhibitors against Mpro and other drug targets of SARS-CoV-2 (Almutairi et al, 2022;Elfiky et al, 2022;Alaa M. Elgohary et al, 2022;Gomha et al, 2022;Ibrahim et al, 2022;Moriou et al, 2021).…”