Molecular dynamics, molecular docking, DFT, and ADMET investigations of the Co(II), Cu(II), and Zn(II) chelating on the antioxidant activity and SARS-CoV-2 main protease inhibition of quercetin

The natural flavonol quercetin (Q) is found in many vegetables, fruits, and beverages, and it is known as a strong antioxidant. Its metal ion chelation may increase its antioxidant activity. The present study aims to explore the Co(II), Cu(II), and Zn(II) chelating on the antioxidant effectiveness and severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2) main protease (Mpro) inhibitory of quercetin using Density-functional theory (DFT), molecular docking, and molecular dynamics simulations (MD). DFT calculations at the B3LYP/LanL2DZ reveal that the high antioxidant activity of the metal-chelated quercetin complexes is mainly returned to their lower ionization potentials (IPs) compared with the one of the free quercetin. Molecular docking of quercetin and its Co(II), Cu(II), and Zn(II) chelates into the active binding sites of peroxiredoxin 5 and SARS-CoV-2 main protease (Mpro) were performed using Lamarckian Genetic Algorithm method. The docked quercetin and its metal chelates fit well into the binding site of the target proteins, and their binding affinity is strongly influenced by the type of the chelated metals Co(II), Cu(II), and Zn(II), and molar ratio metal: ligand, i.e. 1:2 and 2:1. Further, the binding stability of QZn2 and QCu2 in peroxiredoxin 5 and SARS-CoV-2 main protease targets is evaluated using MD simulation conducted for 100 ns simulations at natural room temperature conditions, and the obtained results showed that all chelates remain bound to the ligand binding groove of protein except for 1HD2_QZn2 complex. Finally, the adsorption, distribution, metabolism, excretion, and toxicity (ADMET) and drug-likeness properties of quercetin and cobalt(II)-quercetin (QCo2(II)) were investigated.Communicated by Ramaswamy H. Sarma.