Design, synthesis, molecular docking, dynamics simulations and antiviral activities of quinoline derivatives

Abstract

The designed and synthesized quinoline derivatives were screened for their anti-RSV, anti-YFV and broad spectrum anti-viral activity. Initially, physicochemical and drug-like properties of all compounds were evaluated then molecular docking and molecular dynamics (MD) simulations were performed on the active site of RSV G (glycoproteins) and Mtase (methyltransferase) enzyme against RSV and YFV respectively. All compounds interacted well with amino acid residues Thr173 (2.85 Å), Ser123 (3.02 Å), Gln89 (3.00 Å), Tyr34 (3.62 Å), Val147 (3.08 Å), Leu46 (3.03 Å), Tyr34 (3.62 Å), Trp96 (2.70 Å) of RSV G protein and with amino acid residues Ile124 (2.94 Å), Phe126 (3.08 Å), Tyr89 (3.77 Å), Arg41 (2.91 Å), Arg37 (2.89 Å), Arg84 (2.97 Å) of the MTase protein, showing their nature as probable inhibitors of RSV and YFV. Antiviral screening revealed that compound 4 was an effective inhibitor against RSV, showing an SI value of 11.6 and an EC50 of 8.6 µg/mL (3.2 × 103 µM), while compound 6 was effective against YFV, with an SI value of 28.5 and an EC50 of 3.5 µg/mL (1.17 × 103 µM). Molecular dynamics parameters, such as RMSD, RMSF, and RGyr, were satisfactory for the 6BLH:4 complex, with a predicted binding energy of -5.64 kcal/mol, which was lower than that of the 6BLH: ribavirin complex (-4.13 kcal/mol). Similarly, the MD parameters for the 3EVA:6 complex were also highly satisfactory. Therefore, compounds 4 and 6 may serve as potential inhibitors against RSV and YFV, respectively.