Toward Novel COVID-19 Therapeutics: In Silico Discovery of Quinine-Based SARS-CoV-2 Mpro Inhibitors

SARS-CoV-2 variants continue to pose a global health threat. This study evaluated twenty-one quinine derivatives as potential inhibitors of the viral main protease (Mpro) using an integrated in silico workflow combining molecular docking, molecular dynamics (MD) simulations and pharmacokinetic profiling. Docking identified Indole-5,6-quinine and quinine glucuronide as the top candidates (−8.3 and −8.2 kcal/mol, respectively). ADME assessment with SwissADME showed that several derivatives comply with Lipinski’s rule of five and exhibit acceptable drug-likeness. MD simulations of representative ligand–Mpro complexes demonstrated sustained stability over production runs, with Indole-5,6-quinine showing the lowest root-mean-square deviation (RMSD), consistent with a tightly bound complex. Correlation analysis revealed a moderate negative association between the number of hydrogen-bond acceptors and binding free energy (ΔG) (Spearman’s ρ ≈ −0.54), suggesting that additional acceptor groups may favor stronger binding. Interaction mapping highlighted hydrogen bonds and hydrophobic contacts as principal stabilizing forces at the active site. Taken together, docking, dynamic stability and ADME profiling nominate several quinine derivatives, notably Indole-5,6-quinine and quinine glucuronide, as promising Mpro inhibitors that warrant experimental validation.