We were interested to probe the binding impact of dexamethasone with SARS-CoV-2 Spike RBD and in particular RBD of strain XBB.1.5. Here we considered binding analysis for five strains (Omicron, BJ.1, BM.1.1.1, XBB and XBB) and wild type. The emergence of strain XBB has been reported a recombinant strain BJ.1 and BM.1.1.1, that further evolved to strain XBB.1.5. All these four strains belong to the Omicron lineage which itself is evolved from the wild type strain [3]. To comparatively analyze all these mentioned strains, we used the former five as control.

Dexamethasone targeted the middle pocket enclosed by the two smaller α helices located below the ACE2 binding interface, and showed binding energies of -8.4, -11.1, -9.8, -11.1, -9.6 and -12.0 Kcalmol−1 with RBD wild type, Omicron, BJ.1, BM.1.1.1, XBB and XBB.1.5, respectively. However, dexamethasone did not prefer the same pocket and docked to the dorsal side of pocket in Omicron variant (Fig. 1). To confirm any aberrant changes in RBD static structures brought by mutations, all the structures were aligned and found satisfactory, with RMSD of 0.2–0.5 Å suggesting no major structural aberrations (Additional file 1: Figure S1). One of the apparent reasons we found was 339 mutation (a pocket residue), which was an opposite charged residue in Omicron lineages compared to other members and Glycine in wild type. Aside binding conformations, we observed two hydrogen bonds as well as vdw interactions with S373 and W436 in wild type. In contrast, the Spike proteins of BJ.1 and BM.1.1.1 variant displayed three and two hydrogen bonds with V362, D364 and A372, N437 assisted by vdW effects. With the Spike RBD of strain XBB, dexamethasone was able to form hydrogen bond interaction with A344, T346 and R506 along with N343, F342, T345, F375, W436 and L441 observed in vdW interactions. The RBD of strain XBB.1.5, engaged the polar oxygen of dexamethasone and formed two hydrogen bonds with D364 and V362. Apart from hydrogen bonds, we found residues L335, C336, F338, H339, F342, N343, A363, V367, I368 and L371 involved in vdW interactions (Fig. 2).

Binding and Energetics Analysis of Dexamethasone against SARS-CoV-2 RBD. A, Distribution of dexamethasone binding preferences against the strains of SARS-CoV-2. B, Two-dimensional representation of Dexamethasone interaction against the SARS-CoV-2 RBDs of Wild type, variant Omicron, BJ.1, BM.1.1.1, XBB and XBB.1.5, respectively

Residue Contributions in Binding of Dexamethasone against SARS-CoV-2 RBD. A, SARS RBD differences at amino acid level among different strains. B, Details of the binding pocket and residue of the SARS-CoV-2 RBDs of Wild type, variant Omicron, BJ.1, BM.1.1.1, XBB and XBB.1.5, for Dexamethasone

Dexamethasone is a powerful immunosuppressive agent with powerful anti-inflammatory effect, which can fundamentally inhibit the inflammatory response of the body against viral infection, reduce endogenous pyrogen, and inhibit the response of the hypothalamus, with obvious cooling and antipyretic effect. However, dexamethasone, as a hormone drug, has certain side effects and harm, especially for children and people with pre-existing conditions. Therefore, dexamethasone can be used as a temporary antipyretic drug under strict control of dosage when meeting an urgent need, but it cannot be used as a conventional therapy for patients with mild symptoms. The long term use of it will cause a series of side effects, such as hyperglycemia, insulin resistance, lipid metabolism disorder, muscular dystrophy, osteoporosis, etc. Studies have confirmed that physical exercise can improve the side effects caused by long-term use of dexamethasone [4, 5]. For example, low-intensity exercise can improve hyperglycemia and gastric dysmotility and Moderate -intensity aerobic exercise and high-intensity interval exercise can improve insulin resistance and lipid metabolism disorders [4, 5]. Therefore, moderate physical exercise is recommended after treatment with dexamethasone to reduce the side effects caused by it.