Funnel metadynamics and behavioral studies reveal complex effect of D2AAK1 ligand on anxiety-like processes

Damian Bartuzi; Ewa Kędzierska; Katarzyna M. Targowska-Duda; Oliwia Koszła; Tomasz M. Wróbel; Simon Jademyr; Tadeusz Karcz; Katarzyna Szczepańska; Piotr Stępnicki; Olga Wronikowska-Denysiuk; Grażyna Biała; Jadwiga Handzlik; Jesper L. Kristensen; Antti Poso; Agnieszka A. Kaczor

doi:10.1038/s41598-022-25478-7

Funnel metadynamics and behavioral studies reveal complex effect of D2AAK1 ligand on anxiety-like processes

Damian Bartuzi, Ewa Kędzierska, Katarzyna M. Targowska-Duda, Oliwia Koszła, Tomasz M. Wróbel, Simon Jademyr, Tadeusz Karcz, Katarzyna Szczepańska, Piotr Stępnicki, Olga Wronikowska-Denysiuk, Grażyna Biała, Jadwiga Handzlik, Jesper L. Kristensen, Antti Poso, Agnieszka A. Kaczor^*

^*Corresponding author for this work

Medicinal Chemistry

Research output: Contribution to journal › Journal article › Research › peer-review

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17 Downloads (Pure)

Abstract

Anxiety is a troublesome symptom for many patients, especially those suffering from schizophrenia. Its regulation involves serotonin receptors, targeted e.g. by antipsychotics or psychedelics such as LSD. 5-HT_2A receptors are known for an extremely long LSD residence time, enabling minute doses to exert a long-lasting effect. In this work, we explore the changes in anxiety-like processes induced by the previously reported antipsychotic, D2AAK1. In vivo studies revealed that the effect of D2AAK1 on the anxiety is mediated through serotonin 5-HT_1A and 5-HT_2A receptors, and that it is time-dependent (anxiogenic after 30 min, anxiolytic after 60 min) and dose-dependent. The funnel metadynamics simulations suggest complicated ligand-5HT_2AR interactions, involving an allosteric site located under the third extracellular loop, which is a possible explanation of the time-dependency. The binding of D2AAK1 at the allosteric site results in a broader opening of the extracellular receptor entry, possibly altering the binding kinetics of orthosteric ligands.

Original language	English
Article number	21192
Journal	Scientific Reports
Volume	12
Issue number	1
Number of pages	14
ISSN	2045-2322
DOIs	https://doi.org/10.1038/s41598-022-25478-7
Publication status	Published - 2022

Bibliographical note

Funding Information:
The research was funded under OPUS grant from National Science Center (NCN, Poland), Grant Numbers 2017/27/B/NZ7/01767 and UMO-2021/43/B/NZ7/01732 (to A.A.K). Calculations were performed under PRACE European Computing Infrastructure Grants MOLTRANSREC and NERVOMOLSIM (to A.A.K.), Poznań Supercomputing and Networking Center Grant MOLTRANSREC (to A.A.K.), Interdisciplinary Center for Mathematical and Computational Modeling in Warsaw grant, Grant Number G85-948 (to A.A.K) and under resources of CSC Finland. The work was supported by Polish National Agency for Academic Exchange within the Bekker NAWA Programme, project PANALLOS, Grant Number BPN/BEK/2021/1/00408/U/00001 (to D.B.).

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Bartuzi, D., Kędzierska, E., Targowska-Duda, K. M., Koszła, O., Wróbel, T. M., Jademyr, S., Karcz, T., Szczepańska, K., Stępnicki, P., Wronikowska-Denysiuk, O., Biała, G., Handzlik, J., Kristensen, J. L., Poso, A., & Kaczor, A. A. (2022). Funnel metadynamics and behavioral studies reveal complex effect of D2AAK1 ligand on anxiety-like processes. Scientific Reports, 12(1), [21192]. https://doi.org/10.1038/s41598-022-25478-7

Funnel metadynamics and behavioral studies reveal complex effect of D2AAK1 ligand on anxiety-like processes. / Bartuzi, Damian; Kędzierska, Ewa; Targowska-Duda, Katarzyna M.; Koszła, Oliwia; Wróbel, Tomasz M.; Jademyr, Simon; Karcz, Tadeusz; Szczepańska, Katarzyna; Stępnicki, Piotr; Wronikowska-Denysiuk, Olga; Biała, Grażyna; Handzlik, Jadwiga; Kristensen, Jesper L.; Poso, Antti; Kaczor, Agnieszka A.

In: Scientific Reports, Vol. 12, No. 1, 21192, 2022.

Research output: Contribution to journal › Journal article › Research › peer-review

Bartuzi, D, Kędzierska, E, Targowska-Duda, KM, Koszła, O, Wróbel, TM, Jademyr, S, Karcz, T, Szczepańska, K, Stępnicki, P, Wronikowska-Denysiuk, O, Biała, G, Handzlik, J, Kristensen, JL, Poso, A & Kaczor, AA 2022, 'Funnel metadynamics and behavioral studies reveal complex effect of D2AAK1 ligand on anxiety-like processes', Scientific Reports, vol. 12, no. 1, 21192. https://doi.org/10.1038/s41598-022-25478-7

Bartuzi, Damian ; Kędzierska, Ewa ; Targowska-Duda, Katarzyna M. ; Koszła, Oliwia ; Wróbel, Tomasz M. ; Jademyr, Simon ; Karcz, Tadeusz ; Szczepańska, Katarzyna ; Stępnicki, Piotr ; Wronikowska-Denysiuk, Olga ; Biała, Grażyna ; Handzlik, Jadwiga ; Kristensen, Jesper L. ; Poso, Antti ; Kaczor, Agnieszka A. / Funnel metadynamics and behavioral studies reveal complex effect of D2AAK1 ligand on anxiety-like processes. In: Scientific Reports. 2022 ; Vol. 12, No. 1.

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title = "Funnel metadynamics and behavioral studies reveal complex effect of D2AAK1 ligand on anxiety-like processes",

abstract = "Anxiety is a troublesome symptom for many patients, especially those suffering from schizophrenia. Its regulation involves serotonin receptors, targeted e.g. by antipsychotics or psychedelics such as LSD. 5-HT2A receptors are known for an extremely long LSD residence time, enabling minute doses to exert a long-lasting effect. In this work, we explore the changes in anxiety-like processes induced by the previously reported antipsychotic, D2AAK1. In vivo studies revealed that the effect of D2AAK1 on the anxiety is mediated through serotonin 5-HT1A and 5-HT2A receptors, and that it is time-dependent (anxiogenic after 30 min, anxiolytic after 60 min) and dose-dependent. The funnel metadynamics simulations suggest complicated ligand-5HT2AR interactions, involving an allosteric site located under the third extracellular loop, which is a possible explanation of the time-dependency. The binding of D2AAK1 at the allosteric site results in a broader opening of the extracellular receptor entry, possibly altering the binding kinetics of orthosteric ligands.",

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note = "Funding Information: The research was funded under OPUS grant from National Science Center (NCN, Poland), Grant Numbers 2017/27/B/NZ7/01767 and UMO-2021/43/B/NZ7/01732 (to A.A.K). Calculations were performed under PRACE European Computing Infrastructure Grants MOLTRANSREC and NERVOMOLSIM (to A.A.K.), Pozna{\'n} Supercomputing and Networking Center Grant MOLTRANSREC (to A.A.K.), Interdisciplinary Center for Mathematical and Computational Modeling in Warsaw grant, Grant Number G85-948 (to A.A.K) and under resources of CSC Finland. The work was supported by Polish National Agency for Academic Exchange within the Bekker NAWA Programme, project PANALLOS, Grant Number BPN/BEK/2021/1/00408/U/00001 (to D.B.). ",

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AU - Kędzierska, Ewa

AU - Targowska-Duda, Katarzyna M.

AU - Koszła, Oliwia

AU - Wróbel, Tomasz M.

AU - Jademyr, Simon

AU - Karcz, Tadeusz

AU - Szczepańska, Katarzyna

AU - Stępnicki, Piotr

AU - Wronikowska-Denysiuk, Olga

AU - Biała, Grażyna

AU - Handzlik, Jadwiga

AU - Kristensen, Jesper L.

AU - Poso, Antti

AU - Kaczor, Agnieszka A.

N1 - Funding Information: The research was funded under OPUS grant from National Science Center (NCN, Poland), Grant Numbers 2017/27/B/NZ7/01767 and UMO-2021/43/B/NZ7/01732 (to A.A.K). Calculations were performed under PRACE European Computing Infrastructure Grants MOLTRANSREC and NERVOMOLSIM (to A.A.K.), Poznań Supercomputing and Networking Center Grant MOLTRANSREC (to A.A.K.), Interdisciplinary Center for Mathematical and Computational Modeling in Warsaw grant, Grant Number G85-948 (to A.A.K) and under resources of CSC Finland. The work was supported by Polish National Agency for Academic Exchange within the Bekker NAWA Programme, project PANALLOS, Grant Number BPN/BEK/2021/1/00408/U/00001 (to D.B.).

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N2 - Anxiety is a troublesome symptom for many patients, especially those suffering from schizophrenia. Its regulation involves serotonin receptors, targeted e.g. by antipsychotics or psychedelics such as LSD. 5-HT2A receptors are known for an extremely long LSD residence time, enabling minute doses to exert a long-lasting effect. In this work, we explore the changes in anxiety-like processes induced by the previously reported antipsychotic, D2AAK1. In vivo studies revealed that the effect of D2AAK1 on the anxiety is mediated through serotonin 5-HT1A and 5-HT2A receptors, and that it is time-dependent (anxiogenic after 30 min, anxiolytic after 60 min) and dose-dependent. The funnel metadynamics simulations suggest complicated ligand-5HT2AR interactions, involving an allosteric site located under the third extracellular loop, which is a possible explanation of the time-dependency. The binding of D2AAK1 at the allosteric site results in a broader opening of the extracellular receptor entry, possibly altering the binding kinetics of orthosteric ligands.

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