Molecular Docking and Dynamics Simulation of Natural Phenolic Compounds with GSK-3ß: A Putative Target to Combat Mortality in Patients with COVID-19.

OBJECTIVE: In this study, molecular docking analysis was performed to evaluate the binding affinity of 52 plant-based phenolics with the GSK-3ß active sites. Moreover, Molecular Dynamics (MD) simulation was conducted to investigate the stability of interactions between the topranked phenolics and residues within the GSK-3ß active sites. METHODS: Molecular docking and MD simulations were performed using AutoDock and Discovery Studio Client software, respectively. Thereafter, pharmacokinetic and toxicological properties of top inhibitors were predicted using bioinformatics web tools. This study aimed to identify the most effective amino acids involved in the inhibition of GSK-3ß based on the most stabilizing interactions between the residues and compounds, and also by considering the degree centrality in the ligand- amino acid interaction network for GSK-3ß. RESULTS: It was observed that procyanidin and amentoflavone could bind to the GSK-3ß active sites at the picomolar (pM) scale as well as the binding affinity of ΔG binding < -13 kcal/mol, while the inhibition constant for theaflavin 3'-gallate, procyanidin B4, and rutin was calculated at the nanomolar (nM) scale, suggesting that these phenolic compounds can be considered as potential effective GSK-3ß inhibitors. Furthermore, Val70, Ala83, Val135, and Tyr134 were found to be the most important amino acids involved in the inhibition of GSK-3ß. CONCLUSION: The results of the current study may be useful in the prevention of several human disorders, including COVID-19, cancers, Alzheimer's disease, diabetes mellitus, and cardiovascular diseases. However, wet-lab experiments need to be performed in the future.

COVID-19: docking-based virtual screening and molecular dynamics study to identify potential SARS-CoV-2 spike protein inhibitors from plant-based phenolic compounds.

A novel coronavirus, known as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), enters into the host cells through an interaction between its surface spike protein (S-protein) and the angiotensin-converting enzyme 2 receptors, leading to coronavirus disease 2019 (COVID-19). Using effective S-protein inhibitors may reduce the virulence of the virus. Molecular docking was performed to evaluate the binding affinity of 97 phenolic compounds (phenolics) with the SARS-CoV-2 S-protein receptor-binding domain (RBD). Molecular dynamics (MD) simulation was carried out to assess the stability of interactions between top-ranked compounds and S-protein RBD. Pharmacokinetics and toxicity of top-ranked inhibitors were also studied. Furthermore, the essential residues involved in ligand binding, based on the degree of each amino acid in the ligand-amino acid interaction (LAI) network for S-protein, were identified. Molecular docking and MD simulations were performed utilizing the AutoDock and Discovery Studio Client version, respectively. The LAI network was analyzed using the Cytoscape software. Pharmacokinetics and toxicity of top-ranked compounds were studied using bioinformatics webservers. It was estimated that nine of the studied phenolics can bind to the SARS-CoV-2 S-protein at the nanomolar scale with a considerable estimated energy of binding (∆G binding Keywords: COVID-19; drug; molecular docking; molecular dynamics; SARS-CoV-2; spike protein.