Among
20 compounds isolated from the extracts of Ouratea
ferruginea the 5,4′-dihydroxy-7,5′,3′-trimethoxyisoflavone
(9) showed the best inhibitory effect on glutathione S-transferase (GST) and so deserves our attention. In this
work we investigated the preferred molecular structure of 9 in chloroform solution using the density functional theory (DFT)
and molecular dynamics simulation. Comparison between experimental 1H NMR data in CDCl3 solution and calculated chemical
shifts enabled us to precisely determine the conformation adopted
by 9 in solution, which can be used in further theoretical
studies involving interaction with biological targets. Moreover, the
experimental NMR data were used as reference to assess the ability
of DFT based methods to predict 1H NMR spectrum in solution
for organic compounds. Among various DFT functionals the hybrid B3LYP
was the most adequate for the calculation of chemical shifts in what
CH
n
protons are concerned. Regarding the
OH hydrogen, inclusion of explicit CHCl3 solvent molecules
adequately placed around the solute led to good agreement with the
experimental chemical shifts (in CDCl3). It is a well-known
fact that theoretical prediction of chemical shifts for OH hydrogens
poses as a challenge and also revealed that the way the solvent effects
are included in the DFT calculations is crucial for the right prediction
of the whole 1H NMR spectrum. It was found in this work
that a supermolecule solute–solvent calculation with a minimum
of four CHCl3 molecules is enough to correctly reproduce
the 1H NMR experimental profile observed in solution, revealing
that the calculated solvated structure used to reproduce the NMR chemical
shifts is not unique.
Chloroquine
(CQ) and hydroxychloroquine (HCQ) have been standard
antimalarial drugs since the early 1950s, and very recently, the possibility
of their use for the treatment of COVID-19 patients has been considered.
To understand the drug mode of action at the submicroscopic level
(atoms and molecules), molecular modeling studies with the aid of
computational chemistry methods have been of great help. A fundamental
step in such theoretical investigations is the knowledge of the predominant
drug molecular structure in solution, which is the real environment
for the interaction with biological targets. Our strategy to access
this valuable information is to perform density functional theory
(DFT) calculations of 1H NMR chemical shifts for several
plausible molecular conformers and then find the best match with experimental
NMR profile in solution (since it is extremely sensitive to conformational
changes). Through this procedure, after optimizing 30 trial distinct
molecular structures (ωB97x-D/6-31G(d,p)-PCM level of calculation),
which may be considered representative conformations, we concluded
that the global minimum (named M24), stabilized by an
intramolecular N–H hydrogen bond, is not likely to be observed
in water, chloroform, and dimethyl sulfoxide (DMSO) solution. Among
fully optimized conformations (named M1 to M30, and MD1 and MD2), we found M12 (having no intramolecular H-bond) as the most probable structure
of CQ and HCQ in water solution, which is a good approximate starting
geometry in drug–receptor interaction simulations. On the other
hand, the preferred CQ and HCQ structure in chloroform (and CQ in
DMSO-d
6) solution was assigned as M8, showing the solvent effects on conformational preferences.
We believe that the analysis of 1H NMR data in solution
can establish the connection between the macro level (experimental)
and the sub-micro level (theoretical), which is not so apparent to
us and appears to be more appropriate than the thermodynamic stability
criterion in conformational analysis studies.
Azithromycin (AZM) is a well-known macrolide-type antibiotic that has been used in the treatment of infections and inflammations. Knowledge of the predominant molecular structure in solution is a prerequisite for...
The knowledge of the molecular structure in solution is an important information for further molecular modeling studies on the drug interaction with biological targets. In this work we investigated the...
The high-water solubility of flavonoid catechin makes it a promising candidate as a drug in the treatment of various diseases. The formation of Beta-CD-Catechin inclusion complex has been proposed experimentally,...
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