Abstract
The cell membrane is a complex system that consists of lipids, proteins, polysaccharides, and amphiphilic phospholipids. It plays an important role in ADME processes that are responsible for the final pharmaceutical effects of xenobiotics (bioavailability, activity). To study drug-membrane interaction at the molecular level, several high-performance liquid chromatography (HPLC) membrane model systems have been proposed which are mimicking mainly its lipid character. The aim of this work was to study interactions of new synthesized antiepileptic compounds of 4-alkyl-5-(3-chlorophenyl)-2,4-dihydro-3H-1,2,4-triazole-3-thione derivatives with Chirobiotic column containing glycoprotein ligand attached to the silica matrix. The affinity of the analytes to immobilized glycoprotein ligand was examined chromatographically in reversed-phase mode. The thermodynamics of interactions between bioactive compounds and teicoplanin was studied in terms of the van’t Hoff linear relationship ln k vs. 1/T in the range of 5–45 °C. Change in enthalpy (ΔH°), change in entropy (ΔS°) and change in Gibbs free energy (ΔG°) were estimated utilizing graphical extrapolation and interpolation methods. The density functional theory (DFT) approach and docking simulations were used to get the molecular interpretation and prove the obtained experimental results. Cross-correlations of chromatographic and thermodynamic parameters with non-empirical topological and quantum chemical indices suggest that the polarizability of analytes appears to be responsible for the interactions of the tested molecules with teicoplanin and, ultimately, their retention on the column. Experimental and theoretical parameters were subjected to statistical analysis using regression models. Partial least squares (PLS) regression model showed the usefulness of the experimentally measured parameter φ0 (MeOH) to discriminate between anticonvulsant active and inactive 1,2,4-triazole-3-thione derivatives. Obtained results point out the usefulness of interaction of potential anticonvulsants with glycoprotein class of compounds to anticipate their activity.
Highlights
1.1.Introduction livingorganism, organism,xenobiotics xenobiotics undergo undergo many many biochemical biochemical andInIna aliving and biophysical biophysicalprocesses processesthat that are abbreviated as ADME, i.e., adsorption, distribution, metabolism, and elimination.are abbreviated as ADME, i.e., adsorption, distribution, metabolism, and elimination.EachEachofofthese these stagesdepends dependsinin different ways lipophilicity of the xenobiotic.many empirical stages different ways onon thethe lipophilicity of the xenobiotic.many empirical and and non-empirical lipophilicity scales are commonly used to predict the pharmacological activity of non-empirical lipophilicity scales are commonly used to predict the pharmacological activity of potential potential drugs
Two classical models usually used to interpret the dependence of the retention factor (k) on the mobile phase composition and the temperature are described by the Soczewiński-Wachtmeister equation (Section 3.1) known as the linear solvent strength model (LSSM), and the second one concerning thermodynamic studies represented by the Van’t Hoff plot (Section 3.2)
The drug, after administration, biological membranes, i.e., these membranes affects its further biodistribution in the body
Summary
1.1.Introduction livingorganism, organism,xenobiotics xenobiotics undergo undergo many many biochemical biochemical andInIna aliving and biophysical biophysicalprocesses processesthat that are abbreviated as ADME, i.e., adsorption, distribution, metabolism, and elimination.are abbreviated as ADME, i.e., adsorption, distribution, metabolism, and elimination.EachEachofofthese these stagesdepends dependsinin different ways lipophilicity of the xenobiotic.many empirical stages different ways onon thethe lipophilicity of the xenobiotic.many empirical and and non-empirical lipophilicity scales are commonly used to predict the pharmacological activity of non-empirical lipophilicity scales are commonly used to predict the pharmacological activity of potential potential drugs. Are abbreviated as ADME, i.e., adsorption, distribution, metabolism, and elimination.Each. Eachofofthese these stagesdepends dependsinin different ways lipophilicity of the xenobiotic. The process of penetration of exogenous substances through semipermeable membranes can be membranes can be reflected by a partition coefficient. The oldest extra-thermodynamic extraction reflected by a partition coefficient. The oldest extra-thermodynamic extraction system, n-octanol-water, system, n-octanol-water, is considered to be the first model to simulate biological permeability. This is considered to be the first model to simulate biological permeability This two-phase system is a two-phase system is a source of a parameter reflecting the relative lipophilic character of the source of a parameter reflecting the relative lipophilic character of the compound, which is defined by compound, which is defined by log P, where P is the octanol-water partition coefficient [1,2]
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