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Vol. 25, Art. 36 (pp. 648-673)    |    2024       

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Chemoinformatics assisted search for new cyclopeptide ligands of central n cholinoreceptors

Nikiforov A.S., Orlova A.B., Ivanov I.М., Sergeeva S.S., Konovalov A.V., Neeshpapa А.D., Yudin M.A., Chepur S.V.

FSBI «State Research Testing Institute of Military Medicine» of the Ministry of Defense of the Russian Federation, 195043, Russia , Saint-Petersburg, st.Lesoparkovaya, 4, e-mail: gniiivm_15@mil.ru
FSBI «Institute of Physiology named after. I.P. Pavlov» of Russian Academy of Sciences

Brief summary

Central H-cholinergic receptors (nAChRs) are involved in a variety of functions of the central nervous system, as a result of which they can serve as a promising biological target in the development of treatments for Alzheimer's disease, schizophrenia, Parkinson's disease and depression, epilepsy and nicotine addiction. At the same time, the alpha7 subtype of nAChR plays a crucial role in the implementation of cognitive processes. Using the alpha7-nAChR model, a stepwise virtual screening of libraries of octapeptides cyclized through a disulfide bond was carried out, based on the results of which candidate compounds with the sequences VHCHRCYW, RFCRQCRP, FWCEFCEY, EGCHPCPR were selected and built by solid-phase synthesis. The biological activity of octapeptides was assessed using a battery of tests (nicotine convulsions in mice, holding rats on a grid, spike activity of the Retzius neuron of a medicinal leech) using pharmacological probing methods. In samples RFCRQCRP and VHCHRCYW, peripheral N-anticholinergic activity was detected, which in the last one was also combined with potential central anticholinergic properties. Octapeptide EGCHPCPR had an N-cholinomimetic properties.


Key words

сholinergic neurotransmitter system, N-cholinergic receptors, docking, virtual screening, solid-phase peptide synthesis, cyclopeptides, pharmacological probing

Reference list

1. Nickell J.R., Grinevich V.P., Siripurapu K.B. et al. Potential therapeutic uses of mecamylamine and its stereoisomers. Pharmacology Biochemistry and Behavior. 2013; 108: 28-43.


2. Colombo S.F., Mazzo F., Pistillo F., Gotti, C. Biogenesis, trafficking and up-regulation of nicotinic ACh receptors. Biochemical pharmacology. 2013; 86(8): 1063-1073.


3. D'Andrea M.R., Nagele, R.G. Targeting the alpha 7 nicotinic acetylcholine receptor to reduce amyloid accumulation in Alzheimer's disease pyramidal neurons. Current pharmaceutical design. 2006; 12(6): 677-684.


4. Olincy A., Harris J.G., Johnson L.L. et al. Proof-of-concept trial of an α7 nicotinic agonist in schizophrenia. Archives of general psychiatry. 2006; 63(6): 630-638.


5. Balfour D.J. The neurobiology of tobacco dependence: a preclinical perspective on the role of the dopamine projections to the nucleus. Nicotine & Tobacco Research. 2004; 6(6): 899-912.


6. Hone A.J., McIntosh J.M. Nicotinic acetylcholine receptors in neuropathic and inflammatory pain. FEBS letters. 2018; 592(7): 1045-1062.


7. Hone A.J., Servent D., McIntosh J.M. α9‐containing nicotinic acetylcholine receptors and the modulation of pain. British journal of pharmacology. 2018; 175(11): 1915-1927.


8. Levin E.D., McClernon F.J., Rezvani A.H. Nicotinic effects on cognitive function: behavioral characterization, pharmacological specification, and anatomic localization. Psychopharmacology. 2006; 184: 523-539.


9. Spirova E.N. Analiz mishechnih i neironalnih nikotinovih receptorov sochetaniem kalcievogo imidjinga i elektrofiziologii: dis. kand. biol.nayk: 03.01.03. Moskva, 2019. 118 s.


10. Orlova A.B., Nikiforov A.S., Ivanov I.M., Ryipo V.S. Sposobi himicheskoi modifikacii peptidov dlya povisheniya ih peroralnoi biodostypnosti (obzor literatyri). Medline.ru. 2023; 24: 1097-1110.


11. Ho T.N., Abraham N., Lewis R.J. Structure-function of neuronal nicotinic acetylcholine receptor inhibitors derived from natural toxins. Frontiers in Neuroscience. 2020; 14: 609005.


12. Jaghoori M.M., Bleijlevens B., Olabarriaga S.D. 1001 Ways to run AutoDock Vina for virtual screening. Journal of computer-aided molecular design. 2016; 30(3): 237-249.


13. Espinoza-Fonseca L.M. Molecular docking of four β-amyloid1-42 fragments on the α7 nicotinic receptor: delineating the binding site of the Aβ peptides. Biochemical and biophysical research communications. 2004; 323(4): 1191-1196.


14. Espinoza-Fonseca L.M. Base docking model of the homomeric α7 nicotinic receptor-β-amyloid1-42 complex. Biochemical and biophysical research communications. 2004; 320(2): 587-591.


15. Gao X., Guan Y., Wang C. et al. Specific interaction from different Aβ42 peptide fragments to α7nAChR-A study of molecular dynamics simulation. Journal of Molecular Modeling. 2024; 30(7): 233.


16. Espinoza-Fonseca L.M., Trujillo-Ferrara J.G. Fully flexible docking models of the complex between α7 nicotinic receptor and a potent heptapeptide inhibitor of the β-amyloid peptide binding. Bioorganic & medicinal chemistry letters. 2006; 16(13): 3519-3523.


17. Cao X., Liu T., Wang T. et al. De Novo Screening and Mirror Image Isomerization of Linear Peptides Targeting α7 Nicotinic Acetylcholine Receptor. ACS Chemical Biology. 2024: 19(3): 592-598.


18. Zhang B., Ren M., Yang F. et al. Oligo-basic amino acids, potential nicotinic acetylcholine receptor inhibitors. Biomedicine & Pharmacotherapy. 2022; 152: 113215.


19. Diankin I.D., Kudryavtsev D.S., Zalevsky A.O. et al. New Binding Mode of SLURP Protein to a7 Nicotinic Acetylcholine Receptor Revealed by Computer Simulations. Supercomputing Frontiers and Innovations. 2018; 5(4): 73-77.


20. Gulsevin A., Meiler J. An investigation of three-finger toxin—nAChR Interactions through Rosetta protein docking. Toxins. 2020; 12(9): 598.


21. Leffler A.E., Kuryatov A., Zebroski H.A. et al. Discovery of peptide ligands through docking and virtual screening at nicotinic acetylcholine receptor homology models. Proceedings of the National Academy of Sciences. 2017; 114(38): E8100-E8109.


22. Vereshagin V.V., Ivanov I.M., Nikiforov A.S., Golosov R.D. Svidetelstvo o gosydarstvennoi registracii programmi dlya EVM №2022612627 Rossiiskaya Federaciya. Programma dlya sozdaniya konfigyracionnogo faila dlya provedeniya molekylyarnogo dokinga v programmah na osnove Autodock Vina: № 2022612269: zayavl. 18.02.2022: opybl. 28.02.2022.


23. Salentin S., Schreiber S., Haupt V.J. et al. PLIP: fully automated protein-ligand interaction profiler. Nucleic acids research. 2015; 43(W1): W443-W447.


24. Duffy F.J., Verniere M., Devocelle M. et al. CycloPs: generating virtual libraries of cyclized and constrained peptides including nonnatural amino acids. Journal of chemical information and modeling. 2011; 51(4): 829-836.


25. Morris G.M., Huey R., Lindstrom W. et al. AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility. Journal of computational chemistry. 2009; 30(16): 2785-2791.


26. Trott O., Olson A.J. AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. Journal of computational chemistry. 2010; 31(2): 455-461.


27. Potapkin A.M., Lebedev A.A., Bichkov E.R. i dr. Issledovanie protivosydorojnih svoistv novih antagonistov glytamatnih receptorov. Obzori po klinicheskoi farmakologii i lekarstvennoi terapii. 2015; 13(2): 3-9.


28. Ivanov I.M., Orlova A.B., Neeshpapa A.D. i dr. Poisk ciklicheskih peptidnih ligandov perifericheskih N-holinoreceptorov pri pomoshi metodov hemoinformatiki. Medline.ru. 2022; 23: 733-747.


29. Burgin A.M., Szczupak L. Basal acetylcholine release in leech ganglia depolarizes neurons through receptors with a nicotinic binding site. Journal of experimental biology. 1998; 201(12): 1907-1915.


30. Mann H.B., Whitney D.R. On a test of whether one of two random variables is stochastically larger than the other. The annals of mathematical statistics. 1947; 50-60.


31. Corder G.W., Foreman D.I. Nonparametric Statistics for Non-Statisticians: A Step-by-Step Approach. New York: Wiley, 2009.


32. Genes V.S. Tablici dostovernih razlichii mejdy gryppami nabludenii po kachestvennim pokazatelyam: posobie po statisticheskoi obrabotke rezyltatov nabludenii i opitov v medicine i biologii. M.: Medicina; 1964.

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