2. Material and methods
That experimental CIF file determined for Chloroquine
Bis(dihydrogenphosphate) Dihydrate by X-ray diffraction by Karle and
Karle was used as an initial theoretical structure for S(-) form of CQ
because it has a chiral C and, for this reason, two enantiomeric S(-)
and R(+) forms are expected for this antiviral agent [2]. Then, the
R(+) form was modelled with the GaussView program [54] and,
after that, both species were optimized in gas phase and aqueous
solution by using the functional hybrid B3LYP/6-311++G** level of theory
with the Revision A.02 of Gaussian 09 program [55]. Universal
solvation and IEFPCM methods consider the solvent effects and, they were
used to optimize the two forms in aqueous solution [35-37,56-58].
The variations of volumes that both forms experiment in solution were
computed at the same level of theory with the Moldraw program [59].
The NBO and AIM 2000 programs were used together with the Merz-Kollman
charges to calculate atomic charges, molecular electrostatic potentials,
acceptors-donors energies and topological properties [60-63]. On the
other hand, the ultraviolet-visible spectra for both forms in aqueous
solution were predicted with the time-dependent DFT calculations
(TD-DFT) while the 1H and NMR chemical shifts for the
two enantiomeric forms were calculated with the GIAO in the same medium
[64]. The vibrational analyses were performed with the scaled
mechanical force field (SQMFF) methodology, the normal internal
coordinates, transferable scaling factors and the Molvib program
[38-40]. To perform the vibrational assignments potential energy
distribution (PED) contributions ≥ 10 % were used while the predicted
Raman spectra in activities of both forms were corrected to intensities
with equations reported in the literature [65,66]. In addition, the
gap values were computed as the differences between HOMO and LUMO
energies while widely- known equations were used to calculated the
chemical potential (μ ), electronegativity (χ ), global
hardness (η ), global softness (S ), global electrophilicity
index (ω ) and global nucleophilicity index (E ) descriptors
[42-47]. The experimental available infrared, 1H
and NMR and ultraviolet-visible spectra of CQ were taken of those
previously reported in the literature [1]. The calculated properties
for the two enantiomeric S(-) and R(+) forms of CQ were compared with
those reported for other antiviral agents [42-47]. In addition, the
Hirshfeld surfaces (3D) and fingerprint plots (2D) were performed for
the S(-) form of CQ to a complete structural description with Crystal
Explorer 3.1 software [67] imported on CIF files. Finally, the
different structures of COVID-19 enzyme (codes: 6M03 [68], 5R7Y
[69], 6W63 [70], 5R81 [71] and 5R84 [72]) are exported
from Protein Data Bank of the Structural Bioinformatics Research
Laboratory (RCSB) [73]. The preparation of these enzymes for docking
calculations was made using Discovery Studio program [74] .
Molecular docking analysis was performed by using iGEMDOCK software
[75] through the generic evolutionary method (GA) and an
empirical scoring function, with the following setting: population size
is 800, number 10 of generations is 80 and number of solutions is 10.
Intermolecular interactions between COVID-19 protein and Chloroquine for
the best docked states have been visualized in Discovery Studio program.