Investigation of NMDA Receptor Channel Blockers in a Series of Methylene Blue Conjugates Using QSAR and Molecular Modeling
1Institute of Physiologically Active Compounds of the Russian Academy of Sciences,
1 Severnyi pr., Chernogolovka, 142432 Russia; *e-mail: email@example.com
2Institute of Biomedical Chemistry, 10 Pogodinskaya str., Moscow, 119121 Russi
Keywords:NMDAR; channel blockers; QSAR; docking
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 2. The hydrogen bond between the carbonyl group of a ligand (compound 17) and the side chain of Thr646А-GluN17.
Table 1. The formulas, biological activity (IC50mkM) and descriptors (α (Å3), Σ(Ca), Σ(Ca)/α, Eamax) of investigated compounds.
Table 1. Statistical characteristics of QSAR models of NMDA receptor blockade.
Table 3. The numbers of compounds, their experimental (Aexp), calculated (Acalc) activity values, and differences (Δ= Aexp - Acalc) of them in test set.
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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