An insight into the simulation directed understanding of the mechanism in SARS CoV-2 N-CTD, dimer integrity, and RNA-binding: Identifying potential antiviral inhibitors

Coronavirus 2019 is a transmissible disease and has caused havoc throughout the world. The present study identifies the novel potential antiviral inhibitors against the nucleocapsid C-terminal domain that aids in RNA-binding and replication. A total of 485,629 compounds were screened, and MD was performed. The trajectory analysis (DCCM & PCA), structural integrity, and degree of compaction depicted the protein-ligand complex stability (PDB-PISA and R_gyr). Results obtained from screening shortlists 13 compounds possessing high Docking score. Further, seven compounds had a permissible RMSD limit (3 Å), with robust RMSF. Post-MD analysis of the top two compounds (204 and 502), DCCM & PCA analysis show a positive atomic displacements correlation among residues of active sites-dimer (Chain A and Chain B) & residual clustering. The ΔG_int of RNA-bound (-83.5 kcal/mol) and drug-bound N-CTD-204 (-40.8 kcal/mol) and 502(-39.7 kcal/mol) as compared to Apo (-35.95 kcal/mol) suggests stabilization of protein, with less RNA-binding possibility. The R_gyr values depict the loss of compactness on RNA-binding when compared to the drug-bound N-CTD complex. Further, overlapping the protein complexes (0 ns and 100 ns) display significant changes in RMSD of the protein (204-2.07 Å and 502-1.89 Å) as compared to the Apo (1.72 Å) and RNA-bound form (1.76 Å), suggesting strong interaction for compound 204 as compared to 502. ADMET profiling indicates that these compounds can be used for further experiments (in vitro and pre-clinical). Compound 204 could be a promising candidate for targeting the N-protein-RNA assembly and viral replication.