Assessing the binding affinity of glucocorticoids to the SARS-CoV-2 spike protein – angiotensin-converting enzyme 2 complex: a molecular docking simulation study

Background. SARS-CoV-2 has been identified as the causative agent of COVID-19. Viral infection occurs through the interaction of the viral spike protein (S protein) with the host’s angiotensin-converting enzyme 2 (ACE2). In moderate and severe cases of COVID-19, the therapeutic benefits of glucocorticoids are attributed to their ability to mitigate immune-mediated lung injury and suppress the cytokine storm. This study aims to evaluate the binding affinity of glucocorticoids to the S protein–ACE2 complex in two SARS-CoV-2 variants: the wild-type Wuhan strain and the JN.1 subvariant of Omicron, to identify potential glucocorticoid binding sites and the amino acid residues involved in ligand interactions. Materials and Methods. Two crystal structures of the S protein–ACE2 complexes (PDB IDs: 6M0J and 8Y18 from the Protein Data Bank) were selected as docking targets. Molecular docking was performed to assess the binding affinity of dexamethasone (DEX), methylprednisolone (Medrol), and triamcinolone (TAC) to the S protein–ACE2 complex. Docking results were visualized using PyMol 2.5. The protein-ligand interaction profiler (PLIP) was employed to identify non-covalent interactions between proteins and ligands. The root mean square fluctuation (RMSF) of amino acid residue was quantified using CABS-flex 2.0 software. Results and Discussion. Using a molecular docking approach, it has been demon­strated that DEX, Medrol, and TAC form energetically favorable interactions with both the 6M0J and 8Y18 structures, exhibiting low binding energy scores: 6M0J-DEX -8.0 kcal/mol; 6M0J-Medrol -7.8 kcal/mol; 6M0J-TAC -8.3 kcal/mol; 8Y18-DEX -8.4 kcal/mol; 8Y18-Medrol -8.3 kcal/mol; 8Y18-TAC -8.7 kcal/mol. However, the binding affinities of these complexes differ due to mutations in the S protein, which alter the polarity distribution of its amino acid residues, particularly their ability to form hydrogen bonds. Conclusion. Studying the binding parameters of DEX, Medrol, and TAC with the S protein–ACE2 complex is essential, particularly given SARS-CoV-2’s capacity for rapid mutation. Certain mutations can alter binding sites, potentially influencing drug efficacy. Docking studies that analyze the energetic and structural characteristics of glucocorticoid binding pockets on the S protein–ACE2 complex can help predict how molecular interactions may change as the virus mutates.