Abstract
The encapsulation mode of dexamethasone (Dex) into the cavity of β-cyclodextrin (β-CD), as well as its potential as an inhibitor of the COVID-19 main protease, were investigated using density functional theory with the recent dispersion corrections D4 and molecular docking calculations. Independent gradient model and natural bond orbital approaches allowed for the characterization of the host–guest interactions in the studied systems. Structural and energetic computation results revealed that hydrogen bonds and van der Waals interactions played significant roles in the stabilization of the formed Dex@β-CD complex. The complexation energy significantly decreased from −179.50 kJ/mol in the gas phase to −74.14 kJ/mol in the aqueous phase. A molecular docking study was performed to investigate the inhibitory activity of dexamethasone against the COVID-19 target protein (PDB ID: 6LU7). The dexamethasone showed potential therapeutic activity as a SARS CoV-2 main protease inhibitor due to its strong binding to the active sites of the protein target, with predicted free energy of binding values of −29.97 and −32.19 kJ/mol as calculated from AutoDock4 and AutoDock Vina, respectively. This study was intended to explore the potential use of the Dex@β-CD complex in drug delivery to enhance dexamethasone dissolution, thus improving its bioavailability and reducing its side effects.
Highlights
Dexamethasone is a synthetic glucocorticoid—a cheap and well-known drug approved by the FDA in 1958 [1] for which pharmacokinetics studies are well-established—that presents anti-inflammatory and immunosuppressive properties [2,3]
The results from the RECOVERY trial indicated that dexamethasone treatment helped to reduce mortality in patients that were mechanically ventilated by one-third and by one-fifth in patients only getting oxygen without invasive mechanical ventilation
The analysis of structural, energetic, and electronic properties using independent gradient model (IGM) and natural bond orbital calculation (NBO) allowed us to characterize the nature of the host–guest interactions in the Dex@βCD complex
Summary
Dexamethasone is a synthetic glucocorticoid—a cheap and well-known drug approved by the FDA in 1958 [1] for which pharmacokinetics studies are well-established—that presents anti-inflammatory and immunosuppressive properties [2,3]. Thanks to its potential to reduce lung inflammation and decrease ARDS severity [8], dexamethasone was the first medication to show efficiency in saving lives of coronavirus disease patients [9]. Several randomized clinical trials (RCTs) have been carried out in the United Kingdom [10], Brazil [11], Argentina [12], and other countries using dexamethasone to assess its effectiveness in reducing the mortality risk of patients. A large-scale randomized study comparing 2104 patients receiving the oral or intravenous injection of dexamethasone (6 mg once per day for 10 days with 4321 patients receiving standard care [13,14]) was conducted in the United Kingdom (the RECOVERY trial) for hospitalized patients. The efficacy of dexamethasone was only proven for patients requiring respiratory support—not for milder cases where it was not significant [15,16]
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