Biomedical Chemistry: Research and Methods 2019, 2(2), e00091

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

V.Y. Grigorev1*, K.A. Shcherbakov2, D.E. Polianczyk1, А.N. Razdolsky1, A.V. Veselovsky1,2, V.V. Grigoriev1, A.V. Yarkov1, О.А. Raevsky1

1Institute of Physiologically Active Compounds of the Russian Academy of Sciences,
1 Severnyi pr., Chernogolovka, 142432 Russia; *e-mail: beng@ipac.ac.ru
2Institute of Biomedical Chemistry, 10 Pogodinskaya str., Moscow, 119121 Russi

Keywords:NMDAR; channel blockers; QSAR; docking

DOI:10.18097/BMCRM00091

The whole version of this paper is available in Russian.

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.
Figure 1. The structure formulas of methylene blue conjugates.
Figure 2. The hydrogen bond between the carbonyl group of a ligand (compound 17) and the side chain of Thr646А-GluN17.
Figure 3. The possible hydrogen bond between compound 29 and side chain Asn609D-GluN2B.

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Table 1. The formulas, biological activity (IC50mkM) and descriptors (α (Å3), Σ(Ca), Σ(Ca)/α, Eamax) of investigated compounds.

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Table 1. Statistical characteristics of QSAR models of NMDA receptor blockade.

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Table 3. The numbers of compounds, their experimental (Aexp), calculated (Acalc) activity values, and differences (Δ= Aexp - Acalc) of them in test set.

ACKNOWLEDGEMENTS

The work was performed within the framework of the state task of the IPAC RAS for 2019 (topic number 0090-2019-0004).

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