ABSTRACT
Various clinical trials are undergoing to identify specific drugs for the treatment of new global threat viruses. The main protease of SARS-CoV-2 is one of the significant targets to design and amplify antiviral drugs. In this investigation, we optimized a nucleoside, uridine, and some of its acylated derivatives (2-14) using density functional theory (DFT) at the B3LYP/3-21G level of theory. Charge distribution, polarizability, and thermodynamic properties such as free energy, heat capacity, entropy, of modified compounds were studied in the subsequent analysis to evaluate how certain groups (aliphatic and aromatic) impact the drug properties. It was observed that all derivatives were thermodynamically more stable than the parent ligand, uridine, and some of them were more chemically reactive than others. Then, molecular docking was performed against SARS-CoV-2 main protease (PDB: 6Y84 and 6LU7) to investigate the binding mode (s) and binding affinities of the selected uridine derivatives. Most of the compounds studied here could bind near the crucial catalytic residues, HIS41 and CYS145 of the main protease and surrounded by other active site residues such as GLY143, MET49, MET165, HIS163, PRO168, GLU166, GLN189 and SER144. Significant binding affinities (-6.0 to -7.8 kcal mol(-1)) for 6LU7 and (-5.9 to -7.7 kcal mol(-1)) for 6Y84 were found which revealed the potency of inhibition of uridine derivatives against SARS-CoV-2 M-pro. Finally, all the modified uridine derivatives were analyzed in silico ADMET and drug-like properties. Overall, the present study could be helpful for the development of uridine-based novel potential inhibitors against the SARS-CoV-2 M-pro.