Ligands affinity for regulatory sites of human acetylcholesterase and butyrylcholinesterase: A comparative bioinformatic analysis

A.R. Mukhametgalieva*, A.S. Kozlova**, N.I. Akberova***, A.N. Fattakhova****

Kazan Federal University, Kazan, 420008 Russia

E-mail: *aliya_rafikovna@mail.ru, ​**kozlovanastasiaser@gmail.com, ***nakberova@mail.ru, ****afattakh57@gmail.com

Received August 31, 2020


ORIGINAL ARTICLE

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DOI: 10.26907/2542-064X.2021.1.5-19

For citation: Mukhametgalieva A.R., Kozlova A.S., Akberova N.I., Fattakhova A.N. Ligands affinity for regulatory sites of human acetylcholesterase and butyrylcholinesterase: A comparative bioinformatic analysis. Uchenye Zapiski Kazanskogo Universiteta. Seriya Estestvennye Nauki, 2021, vol. 163, no. 1, pp. 5–19. doi: 10.26907/2542-064X.2021.1.5-19. (In Russian)

Abstract

Cholinesterase inhibitors have been the subject of many studies aimed at developing an effective treatment for various cognitive disorders. Therefore, studying cholinesterases and elucidating the mechanism of their interaction with ligands provide a basis for targeted synthesis and selection of highly specific reversible inhibitors. We analyzed the affinity of the cholinesterase substrates and inhibitors to identify the differences in the ligands binding to the acetylcholinesterase and butyrylcholinesterase active sites by molecular docking. Ligands with a benzene ring had better affinity for the regulatory sites of acetylcholinesterase and butyrylcholinesterase. The lowest affinity for enzymes was found in choline, a hydrolysis product of natural acetylcholine, and in tetramethylammonium, a choline derivative. Differences in the binding of acetylcholine and choline molecules within the acyl pocket of the active site of cholinesterases were shown.

Keywords: acetylcholinesterase, butyrylcholinesterase, molecular docking, energy of affinity, acetylcholine, choline

Acknowledgments. The study was supported by the Russian Foundation for Basic Research (project no. 19-34-90120).

Figure Captions

Fig. 1. Compounds used as ligands.

Fig. 2. Affinity statistics for the positions of ligands in the regulatory sites; p < 0.05. Differences between the affinity energy values of acetylcholinesterase and butyrylcholinesterase with ligands are shown with color. Ligands on the X-axis have better affinity for the protein than ligands on the Y-axis within this enzyme site. Positive values of the difference between the means (dark blue) indicate lower affinity; negative values (red) show better affinity.

Fig. 3. Interaction of acetylcholinesterase and butyrylcholinesterase amino acids with ligands. Positions of the amino acids: pink color – in acetylcholinesterase, blue color – in butyrylcholinesterase, black color – in both enzymes; p > 0.05.

Fig. 4. Position of acetylcholine and choline in the acyl pocket of acetylcholinesterase and butyrylcholinesterase; colors for the active site regions under study: acyl pocket – green, peripheral anionic site – blue, anionic site – dark blue, catalytic triad – pink, oxyanion hole – orange. Ligands shown in green are characterized by high affinity energy values. Ligands highlighted in red have low affinity energy values. Amino acids interacting with acetylcholine and choline are indicated.

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