Computational investigation of novel synthetic analogs of C-1'β substituted remdesivir against RNA-dependent RNA-polymerase of SARS-CoV-2.

Remdesivir, a C-nucleotide prodrug binds to the viral RNA-dependent-RNA polymerase () and inhibits the viral replication by terminating RNA transcription prematurely. It is reported in literature that interaction between the C-1'β-CN moiety of Remdesivir () and the Ser861 residue in enzyme, causes a delayed chain termination during the RNA replication process and is one of the important aspect of its mechanism of action. In the pursuance of increasing the biological activity of and enhancing the SAR studies, against RNA viruses, we have designed its fourteen C1'β substituted analogs, - bearing 4/5-membered heterocyclic rings. The docking and 100 ns molecular dynamics (MD) simulations of - to the protein (PDB ID: 7L1F) revealed important interactions between 2',3'-diol, oxo group of phosphoramidate, nitrogen residues of heterocyclic rings of synthetic molecules with Arg555, Arg553, Ser759, Cys622, Asn691, Asp623 amino acid residues of protein. The docking score of 2-ethylbutyl ((S)-(((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-3,4-dihydroxy-5-(1H-1,2,3-triazol-4-yl)tetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate, was found to be the higher than among 14 new compounds i.e. -5.20 kcal/mol. Out of 3 compounds, , and submitted for MD simulations and Molecular Mechanics Poisson-Boltzmann Surface Area (MMPBSA) analysis, trifluoro-oxadiazole derivative, showed higher binding energy as compared to Remdesivir. The predicted ADMET properties of 14 compounds showed their potential for being drug candidates. The present study suggests that substitution at the C1'β position by 4/5-membered rings plays an important role in the interactions between nucleoside/tide and target protein.