Binding characteristics of systemic glucocorticoids to the SARS-CoV-2 spike glycoprotein: <i>In silico</i> evaluation

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) poses a serious threat to people worldwide causing a variety of diseases, manifesting with intestinal, respiratory, hepatic, and neurological symptoms. The therapeutic strategy to counteract SARS-CoV-2 encompasses antiviral drugs, monoclonal antibodies, as well as immunomodulatory drugs, such as systemic glucocorticoids which may benefit patients with middle and severe COVID-19. The spike glycoprotein (S protein), which recognizes the host cell receptor and initiates the attachment of SARS-CoV-2 to it, can be considered a potential target for glucocorticoids. However, the mechanism of glucocorticoid inhibitory action against the S protein is currently unclear due to insufficient study of the ligand-binding sites on the S protein. The aim of the study was to evaluate the binding characteristics of systemic glucocorticoids to the SARS-CoV-2 S protein and to elucidate the topological features of non-covalent ligand-protein complexes. AutoDock Vina was used for molecular docking studies against the SARS-CoV-2 S protein with ligands. Dexamethasone (DEX), methylprednisolone (Medrol), triamcinolone (TAC), and prednisone (PRED) were selected as ligands. The Open Babel 3.1.1 software was used to prepare ligand structures. Two 3D structures of the S protein which have open (RBD-up) and closed (RBD-down) conformations in the receptor-binding domain (PDB ID: 6VYB, and PDB ID: 6VXX), respectively, were used as docking targets (www.rcsb.org). Ligand interactions with amino acid residues were identified using the PLIP web tool (https://plip-tool.biotec.tu-dresden.de). Visualization of docking results was implemented in PyMol 2.5. Docking study demonstrated that all glucocorticoids can bind to multiple sites in the SARS-CoV-2 S protein, including the receptor-binding fragment (S1) and the fusion fragment (S2). Methylprednisolone showed the best affinity with the S protein in RBD-up conformation than other glucocorticoids, with a binding free energy of –9.7 kcal/mole and an inhibition constant value of 0.08⋅10–6 M. Triamcinolone demonstrated a high affinity with the S protein in RBD-down conformation, at which the binding free energy was −8.8 kcal/mole and an inhibition constant value was 0.36⋅10–6 M. Our results show that Gly744, Asp745 and Arg1000 are mainly involved in the stabilization of complexes through the hydrogen bonds. Hydrophobic interactions are primarily mediated by Thr572, Ile587, and Val976. These results are an important basis for the development of potential drugs against SARS-CoV-2.