Investigation of NMDA Receptor Channel Blockers in a Series of Methylene Blue Conjugates Using QSAR and Molecular Modeling

  • V.Y. Grigorev Institute of Physiologically Active Compounds of the Russian Academy of Sciences, 1 Severnyi pr., Chernogolovka, 142432 Russia
  • K.A. Shcherbakov Institute of Biomedical Chemistry, 10 Pogodinskaya str., Moscow, 119121 Russia
  • D.E. Polianczyk Institute of Physiologically Active Compounds of the Russian Academy of Sciences, 1 Severnyi pr., Chernogolovka, 142432 Russia
  • А.N. Razdolsky Institute of Physiologically Active Compounds of the Russian Academy of Sciences, 1 Severnyi pr., Chernogolovka, 142432 Russia
  • A.V. Veselovsky Institute of Physiologically Active Compounds of the Russian Academy of Sciences, 1 Severnyi pr., Chernogolovka, 142432 Russia; Institute of Biomedical Chemistry, 10 Pogodinskaya str., Moscow, 119121 Russia
  • V.V. Grigoriev Institute of Physiologically Active Compounds of the Russian Academy of Sciences, 1 Severnyi pr., Chernogolovka, 142432 Russia
  • A.V. Yarkov Institute of Physiologically Active Compounds of the Russian Academy of Sciences, 1 Severnyi pr., Chernogolovka, 142432 Russia
  • О.А. Raevsky Institute of Physiologically Active Compounds of the Russian Academy of Sciences, 1 Severnyi pr., Chernogolovka, 142432 Russia
Keywords: NMDAR; channel blockers; QSAR; docking

Abstract

29 conjugates of methylene blue and four chemical structures, including derivatives of carbazole, tetrahydrocarbazole, substituted indoles and γ-carboline, combined with a 1-oxopropylene spacer have been studied as channel blockers of the NMDA receptor (binding site of MK-801) by using four QSAR methods (multiple linear regression, random forest, support vector machine, Gaussian process) and molecular docking. QSAR models have satisfactory characteristics. The analysis of regression models at the statistical level revealed an important role of the hydrogen bond in the complex formation. This was also confirmed by the study of modeled by docking complexes. It was found that the increase in the inhibitory activity of the part of compounds could be attributed to appearance of additional H bonds between the ligands and the receptor.

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Published
2019-06-19
Section
EXPERIMENTAL RESEARCH