A Dispersion Corrected DFT Investigation of the Inclusion Complexation of Dexamethasone with β-Cyclodextrin and Molecular Docking Study of Its Potential Activity against COVID-19

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.

Current Status of Quantum Chemical Studies of Cyclodextrin Host–Guest Complexes

“…For example, when it is assumed that the hydrogen bonds between the guest and host molecules are water mediated. Sometimes, inclusion of the solvent effect decreases the complexation energy significantly, as in the case of the dexamethasone and SMD model [89]. However, it must be pointed out that inclusion of a solvent in the calculated system not always results in better (closer to the experimental data) complexation energies.…”

Unveiling the synergy: a combined experimental and theoretical study of β-cyclodextrin with melatonin

“…On the topic of CD inclusion complexes several computational works have been performed in the last few years. [37][38][39] Stachowicz et al studied the different conformations of b-CD in the gas phase at the B3LYP level, featuring the possible H-bond patterns generated by the hydroxymethyl groups of the different glucopyranose units. 40 To investigate the structures of the three most used CDs (a, b and g), some of us have recently applied the r 2 SCAN-3c composite functional obtaining a complete benchmark.…”

Three-in-one: exploration of co-encapsulation of cabazitaxel, bicalutamide and chlorin e6 in new mixed cyclodextrin-crosslinked polymers

“…In order to obtain more information on the host–guest complexation process, computational chemistry calculations on the inclusion of CBX and the R and S isomer of BIC in the βCyD monomer model with a 1 : 1 and 1 : 2 (guest : CyD) stoichiometry, were carried out using DFT methods. 37 …”