The dissertation is devoted to the experimental substantiation of the antiinflammatory, anti-ulcerogenic and antioxidant efficacy of the combined use of
the bioflavonoid quercetin and the innovative alkoxy derivative 1,4-
benzodiazepine propoxazepam in conditions of acute and chronic inflammatory
disorders and supplementing the understanding of the pathogenesis of
perchlorate-induced intoxication.
In order to achieve the goal and solve the tasks of the dissertation, a series
of experimental studies were conducted on laboratory animals using two models
of the inflammatory process, as well as computer modelling in silico. Work with
experimental animals was carried out in compliance with the European
Convention for the Protection of Vertebrate Animals used for Experimental and
other Scientific Purposes (EST No. 123, 1986), the Law of Ukraine ''On
Protection from Cruel Treatment'' No. 1759-VI on 15 December 2009, Directive
2010/63/EU of the European Parliament and of the Council on the protection of
animals used for scientific purposes, and Order No. 249 of the Ministry of
Education and Science, Youth and Sports of Ukraine dated 1 March 2012.
Laboratory rats were kept on a standard diet with free access to drinking water
in the vivarium of the I.I. Mechnikov ONU.
The first stage of the study involved predicting the toxicity of potassium
perchlorate and the pharmacokinetic characteristics of propoxazepam and
quercetin using in silico computer modelling methods. Using the ProTox 3.0
platform, QikProp (Schrödinger), AutoDock and AutoDock Vina software, as well
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as the pkCSM, admetSAR and SwissADME platforms, the properties of potassium
perchlorate, propoxazepam and quercetin were predicted.
According to the prediction results, potassium perchlorate has a high
probability of immunotoxicity (0.99), hepatotoxicity (0.98), cardiotoxicity (0.97)
and neurotoxicity (0.91), as well as carcinogenic (0.80), mutagenic (0.75) and
cytotoxic (0.73) effects; moderate nephrotoxicity (0.62) and respiratory toxicity
(0.61). Within the analysis of potential targets, ProTox 3.0 revealed a predicted
interaction with sodium-iodide symporter (NIS, 0.94), thyroid receptors THRα
(0.81), as well as the blood-brain barrier (BBB) penetration index (0.91),
confirming the potential for induction of systemic oxidative-inflammatory
disorders.
The assessment of propoxazepam ADME parameters using QikProp showed
a high molecular weight of 405.678 Da, high oral absorption (Human Oral
Absorption = 3; Percent = 100%), octanol/water partition coefficient QPlogP/w =
4.452, water solubility QPlogS = −6.082, high permeability through the intestinal
barrier (QPPCaco = 1703.58 nm/s) and through cells (QPPMDCK = 4273.74
nm/s), brain/plasma distribution ratio QPlogBB = 0.05, inhibition prediction
QPlogHERG = −5.337, and #metab = 4, indicating a favourable pharmacokinetic
profile and potential bioavailability of the compound.
Molecular docking of quercetin to the estrogen receptor (1ERR), performed
in AutoDock and AutoDock Vina, showed low binding energy values (-8.7 for
Vina; GScore= −9.38) and the formation of stable hydrogen bonds with amino acid
residues GLU353, ASP351 and HIE524, indicating an agonistic nature of the
interaction. The parameters obtained using pkCSM admetSAR and SwissADME
showed a predicted intestinal absorption of 77.207%, no AMES toxicity, and
quercetin's compliance with the Lipinski's rule of thumb criteria. The combination
of in silico results confirms the molecular rationale for using quercetin and
propoxazepam for further experimental studies of their anti-inflammatory and
antioxidant efficacy in vivo.
