Non-competitive interactions between hydroxychloroquine and azithromycin: Systematic density functional, molecular dynamics, and docking calculations

Abstract

In this study, density functional theory (DFT) and docking calculations were systematically performed to study the non-competitive interaction between Hydroxychloroquine (HCQ) and azithromycin (AZTH). The calculated changes in Gibbs free energy and enthalpy (at 310 K) were positive, indicating the non-spontaneous formation of HCQ-AZTH specifically in water media. Docking calculation confirmed the obtained DFT result as evident from the different binding sites of both drugs to the SARS-CoV-2 main protease and human angiotensin-converting enzyme 2 (ACE2) proteins. The HCQ-AZTH structure revealed enhanced electrochemical properties, suggesting the synergy between HCQ and AZTH without affecting their therapeutic efficacy against SARS-CoV-2.

Keywords: Azithromycin; Density functional theory; Hydroxychloroquine; Molecular docking; SARS-CoV-2.

Graphical abstract

Fig. 1

Calculations in a gas phase of the electrostatic potential isosurfaces (EPS) for the optimized AZTH (a) and HCQ (b) structures where the red and blue represent most negative and most positive EPS.

Fig. 2

(a) The configuration for the structurally optimized AZTH-HCQ complex interacting through their most negative EPS and most positive EPS sites as shown in Fig. 1. The binding energy for this configuration is −18.68 kcal/mol (b) another AZTH-HCQ configuration with binding energy 376.35 kcal/mol.

Fig. 3

Calculated Infrared spectra (calculated with the numerical frequency mode) for HCQ, AZTH, and AZTH-HCQ in both gas phase and water medium.

Fig. 4

Calculated docking interactions of AZTH and HCQ with (a) M^pro protease and (b) ACE2 (or 1R42) protein. The left colored sheets and helixes are 3-dimensional models for the proteins-drugs interactions. The docking energies (affinities) are shown in kcal/mol beneath the corresponding 2D-interaction models shown to the right of the 3-dimensional model. The colored circles in the 2D models show the names of the protein amino acid residues within the interaction pockets.

Fig. 5

The protein–ligand Root-Mean-Square-Deviation (RMSD) as calculated during 0.2 × 10^−9 s (0.2 ns) molecular dynamic simulations. The proteins are 6LU7 (or M^pro) and 1R42 (or ACE2), and the ligands are AZTH and HCQ.

Fig. 6

The calculated HOMO and LUMO isosurfaces for the AZTH-HCQ complex structure in water phase. The value of the plotted isosurfaces is 0.02000 a.u.