In silico Screening and Behavioral Validation of a Novel Peptide, LCGA-17, With Anxiolytic-Like Properties
The aim of the study was to develop better anxiolytics and antidepressants. We focused on GABAA receptors and the α2δ auxiliary subunit of V-gated Ca2+ channels as putative targets because they are established as mediators of efficacious anxiolytics, antidepressants, and anticonvulsants. We further...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2021-08-01
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| Series: | Frontiers in Neuroscience |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fnins.2021.705590/full |
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| author | Anton V. Malyshev Iuliia A. Sukhanova Alexander S. Zlobin Alexander S. Zlobin Alexander S. Zlobin Alexander S. Zlobin Vasilina R. Gedzun Vasilina R. Gedzun Vsevolod V. Pavshintsev Ekaterina V. Vasileva Arthur O. Zalevsky Igor I. Doronin Nikita A. Mitkin Andrey V. Golovin Andrey V. Golovin Andrey V. Golovin Maxim L. Lovat Georgy I. Kovalev Yurii A. Zolotarev Askar R. Kuchumov Gennady A. Babkin Bernhard Luscher Bernhard Luscher |
| author_facet | Anton V. Malyshev Iuliia A. Sukhanova Alexander S. Zlobin Alexander S. Zlobin Alexander S. Zlobin Alexander S. Zlobin Vasilina R. Gedzun Vasilina R. Gedzun Vsevolod V. Pavshintsev Ekaterina V. Vasileva Arthur O. Zalevsky Igor I. Doronin Nikita A. Mitkin Andrey V. Golovin Andrey V. Golovin Andrey V. Golovin Maxim L. Lovat Georgy I. Kovalev Yurii A. Zolotarev Askar R. Kuchumov Gennady A. Babkin Bernhard Luscher Bernhard Luscher |
| author_sort | Anton V. Malyshev |
| collection | DOAJ |
| description | The aim of the study was to develop better anxiolytics and antidepressants. We focused on GABAA receptors and the α2δ auxiliary subunit of V-gated Ca2+ channels as putative targets because they are established as mediators of efficacious anxiolytics, antidepressants, and anticonvulsants. We further focused on short peptides as candidate ligands because of their high safety and tolerability profiles. We employed a structural bioinformatics approach to develop novel tetrapeptides with predicted affinity to GABAA receptors and α2δ. In silico docking studies of one of these peptides, LCGA-17, showed a high binding score for both GABAA receptors and α2δ, combined with anxiolytic-like properties in a Danio rerio behavioral screen. LCGA-17 showed anxiolytic-like effects in the novel tank test, the light–dark box, and the social preference test, with efficacy comparable to fluvoxamine and diazepam. In binding assays using rat brain membranes, [3H]-LCGA-17 was competed more effectively by gabapentinoid ligands of α2δ than ligands of GABAA receptors, suggesting that α2δ represents a likely target for LCGA-17. [3H]-LCGA-17 binding to brain lysates was unaffected by competition with ligands for GABAB, glutamate, dopamine, serotonin, and other receptors, suggesting specific interaction with α2δ. Dose-finding studies in mice using acute administration of LCGA-17 (i.p.) demonstrated anxiolytic-like effects in the open field test, elevated plus maze, and marble burying tests, as well as antidepressant-like properties in the forced swim test. The anxiolytic effects were effectively blocked by bicuculline. Therefore, LCGA-17 is a novel candidate anxiolytic and antidepressant that may act through α2δ, with possible synergism by GABAA receptors. |
| first_indexed | 2024-12-21T07:50:02Z |
| format | Article |
| id | doaj.art-744533a44c374b5489533f40fc433b89 |
| institution | Directory Open Access Journal |
| issn | 1662-453X |
| language | English |
| last_indexed | 2024-12-21T07:50:02Z |
| publishDate | 2021-08-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Neuroscience |
| spelling | doaj.art-744533a44c374b5489533f40fc433b892022-12-21T19:11:07ZengFrontiers Media S.A.Frontiers in Neuroscience1662-453X2021-08-011510.3389/fnins.2021.705590705590In silico Screening and Behavioral Validation of a Novel Peptide, LCGA-17, With Anxiolytic-Like PropertiesAnton V. Malyshev0Iuliia A. Sukhanova1Alexander S. Zlobin2Alexander S. Zlobin3Alexander S. Zlobin4Alexander S. Zlobin5Vasilina R. Gedzun6Vasilina R. Gedzun7Vsevolod V. Pavshintsev8Ekaterina V. Vasileva9Arthur O. Zalevsky10Igor I. Doronin11Nikita A. Mitkin12Andrey V. Golovin13Andrey V. Golovin14Andrey V. Golovin15Maxim L. Lovat16Georgy I. Kovalev17Yurii A. Zolotarev18Askar R. Kuchumov19Gennady A. Babkin20Bernhard Luscher21Bernhard Luscher22Lactocore, Inc., Plymouth, MI, United StatesLactocore, Inc., Plymouth, MI, United StatesLactocore, Inc., Plymouth, MI, United StatesShemyakin and Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences, Moscow, RussiaFaculty of Bioengineering and Bioinformatics, Lomonosov Moscow State University, Moscow, RussiaSirius University of Science and Technology, Sochi, RussiaLactocore, Inc., Plymouth, MI, United StatesDepartment of Human and Animal Physiology, Faculty of Biology, Lomonosov Moscow State University, Moscow, RussiaLactocore, Inc., Plymouth, MI, United StatesFederal State Budgetary Institution, Research Zakusov Institute of Pharmacology, Moscow, RussiaShemyakin and Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences, Moscow, RussiaLactocore, Inc., Plymouth, MI, United StatesLactocore, Inc., Plymouth, MI, United StatesShemyakin and Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences, Moscow, RussiaFaculty of Bioengineering and Bioinformatics, Lomonosov Moscow State University, Moscow, RussiaSirius University of Science and Technology, Sochi, RussiaDepartment of Human and Animal Physiology, Faculty of Biology, Lomonosov Moscow State University, Moscow, RussiaFederal State Budgetary Institution, Research Zakusov Institute of Pharmacology, Moscow, RussiaInstitute of Molecular Genetics of National Research Centre “Kurchatov Institute”, Moscow, RussiaLactocore, Inc., Plymouth, MI, United StatesLactocore, Inc., Plymouth, MI, United StatesDepartment of Biology, The Pennsylvania State University, University Park, PA, United StatesDepartment of Biochemistry and Molecular Biology, The Pennsylvania State University, University Park, PA, United StatesThe aim of the study was to develop better anxiolytics and antidepressants. We focused on GABAA receptors and the α2δ auxiliary subunit of V-gated Ca2+ channels as putative targets because they are established as mediators of efficacious anxiolytics, antidepressants, and anticonvulsants. We further focused on short peptides as candidate ligands because of their high safety and tolerability profiles. We employed a structural bioinformatics approach to develop novel tetrapeptides with predicted affinity to GABAA receptors and α2δ. In silico docking studies of one of these peptides, LCGA-17, showed a high binding score for both GABAA receptors and α2δ, combined with anxiolytic-like properties in a Danio rerio behavioral screen. LCGA-17 showed anxiolytic-like effects in the novel tank test, the light–dark box, and the social preference test, with efficacy comparable to fluvoxamine and diazepam. In binding assays using rat brain membranes, [3H]-LCGA-17 was competed more effectively by gabapentinoid ligands of α2δ than ligands of GABAA receptors, suggesting that α2δ represents a likely target for LCGA-17. [3H]-LCGA-17 binding to brain lysates was unaffected by competition with ligands for GABAB, glutamate, dopamine, serotonin, and other receptors, suggesting specific interaction with α2δ. Dose-finding studies in mice using acute administration of LCGA-17 (i.p.) demonstrated anxiolytic-like effects in the open field test, elevated plus maze, and marble burying tests, as well as antidepressant-like properties in the forced swim test. The anxiolytic effects were effectively blocked by bicuculline. Therefore, LCGA-17 is a novel candidate anxiolytic and antidepressant that may act through α2δ, with possible synergism by GABAA receptors.https://www.frontiersin.org/articles/10.3389/fnins.2021.705590/fullpeptide drugsdrug screeningnovel ligandNMDA receptoralpha(2)delta subunitcomputational approach |
| spellingShingle | Anton V. Malyshev Iuliia A. Sukhanova Alexander S. Zlobin Alexander S. Zlobin Alexander S. Zlobin Alexander S. Zlobin Vasilina R. Gedzun Vasilina R. Gedzun Vsevolod V. Pavshintsev Ekaterina V. Vasileva Arthur O. Zalevsky Igor I. Doronin Nikita A. Mitkin Andrey V. Golovin Andrey V. Golovin Andrey V. Golovin Maxim L. Lovat Georgy I. Kovalev Yurii A. Zolotarev Askar R. Kuchumov Gennady A. Babkin Bernhard Luscher Bernhard Luscher In silico Screening and Behavioral Validation of a Novel Peptide, LCGA-17, With Anxiolytic-Like Properties Frontiers in Neuroscience peptide drugs drug screening novel ligand NMDA receptor alpha(2)delta subunit computational approach |
| title | In silico Screening and Behavioral Validation of a Novel Peptide, LCGA-17, With Anxiolytic-Like Properties |
| title_full | In silico Screening and Behavioral Validation of a Novel Peptide, LCGA-17, With Anxiolytic-Like Properties |
| title_fullStr | In silico Screening and Behavioral Validation of a Novel Peptide, LCGA-17, With Anxiolytic-Like Properties |
| title_full_unstemmed | In silico Screening and Behavioral Validation of a Novel Peptide, LCGA-17, With Anxiolytic-Like Properties |
| title_short | In silico Screening and Behavioral Validation of a Novel Peptide, LCGA-17, With Anxiolytic-Like Properties |
| title_sort | in silico screening and behavioral validation of a novel peptide lcga 17 with anxiolytic like properties |
| topic | peptide drugs drug screening novel ligand NMDA receptor alpha(2)delta subunit computational approach |
| url | https://www.frontiersin.org/articles/10.3389/fnins.2021.705590/full |
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