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

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  • 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
  • Kristensen, Jesper Langgaard
  • Antti Poso
  • Agnieszka A. Kaczor

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.

Original languageEnglish
Article number21192
JournalScientific Reports
Issue number1
Number of pages14
Publication statusPublished - 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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