Molecular Docking and ADMET Prediction Studies of Flavonoids as Multi-Target Agents In COVID-19 Therapy: Anti-Inflammatory and Antiviral Approaches

Abstract

Hyper-inflammatory reactions due to cytokine storm lead to acute respiratory distress syndrome and are responsible for COVID-19 death toll. Thus, the pathways involved in inflammation and SARS-COV-2 replication represent promising therapeutic targets. By employing a computational model, we investigated the effect of plant flavonoids on pro-inflammatory proteins (glucocorticoid receptor [GR], cyclooxygenase-2 [COX-2], and 5-lipoxygenase [LOX] enzymes) and proteins involved in virus replication (main protease [Mpro] and papain-like protease [PLpro]). This in silico study aimed to identify promising flavonoids with anti-inflammatory and antiviral activities (multi-target) for combating COVID-19. The selected target proteins were Mpro (PDB ID: 6LU7), PLpro (PDBID: 6WX4), COX-2 (PDBID: 6COX), LOX (PDBID: 6N2W), and GR (PDBID: 1P93). We conducted molecular docking using PLANTS software and obtained Lipinski’s “Rule-of-Five” parameters and the predicted pharmacokinetic and toxicity profiles using the pkCSM online platform. Results showed that two flavonoids, diosmin and hesperidin, exhibited a low binding score and higher strength than the reference ligands for the target proteins Mpro, PLpro, and LOX. Both compounds interacted with the amino acid residues of the protein targets through hydrogen bonds and showed similar binding patterns to approved drugs and native ligands. The prediction of ADMET and drug-likeness profiles indicated that these two compounds have low toxicity and good pharmacokinetic properties, except for the absorption profile. Therefore, hesperidin and diosmin are promising multi-target agents for COVID-19 treatment through inhibition of inflammatory progression and virus replication.