Напівемпіричний аналіз взаємодії алкоксипохідних 1,4-бенздіазепіну з ГАМКа-рецептором на підставі даних молекулярного докінгу та фармакологічного ефекту

Abstract

Introduction. Pharmacological spectrum of 1.4-benzodiazepine 3-alkoxy derivatives, in contrast to classical substances, has more prominent analgesic properties, but even among the synthesized and studied molecules there are compounds with different magnitude of this effect.The aim of the study – to evaluate the molecular docking parameters of the theoretically generated structures of 1.4-benzodiazepine alkoxy derivatives with the GABA receptor complex and to compare these data with the pharmacological activity of the synthesized compounds.The molecular docking procedure was carried out using the iGEMDOCK v2.1 program, optimized structures of already synthesized and theoretically designed molecules with differing substituents in the ortho position of the phenyl radical and the "7" position of the condensed system are generated in the Avogadro program (v 1.2.0). The average effective doses of compounds (penthylenetetrazole-induced seizures, 120 mg/kg, subcutaneously 30 min after compounds administration) were studied in white mice.The binding energy of all the generated structures is within the ranges of 81.6–96.8 kcal/mol. Virtual docking data analysis of substituted alkoxy derivatives allows identifying several binding sites inherent for 7-chloro- or 7-bromo-substituted benzodiazepine derivatives. The greatest influence on the binding of chlorine-substituted alkoxy derivatives have regions with a high polarity amino acids (16-23 D) and similar hydrophilicity and hydrophobicity. The contribution of Van der Waals and hydrogen interactions to the total binding energy is determined by the presence of halogen (chlorine or bromine). In penthylenetetrazole-induced seizures test the compounds containing the chlorophenyl substituent in the hetero ring were most active (ED50 (0.42±0.10) μmol/kg for the propyloxy derivative and (0.51±0.17) μmol/kg for the ethyloxy derivative) while for the compounds with the phenyl radical, the ED50 value were much higher (5.1±2.7) μmol/kg and (17.75±1.93) μmol/kg, respectively). The analgesic effect is mainly due to the lkoxy derivatives possibility of binding to a center containing residues of basic amino acids.