Affiliations 

  • 1 Department of Food and Life Science, Pukyong National University, 48513 Busan, Republic of Korea
  • 2 Department of Pharmacology and Chemistry, Faculty of Pharmacy, Universiti Teknologi MARA, 42300 Bandar Puncak Alam, Selangor, Malaysia
  • 3 Department of Food Science and Human Nutrition, Jeonbuk National University, 54896 Jeonju, Republic of Korea
J Integr Neurosci, 2023 Jan 05;22(1):10.
PMID: 36722239 DOI: 10.31083/j.jin2201010

Abstract

BACKGROUND: Cholecystokinin (CCK) is one of the most abundant peptides in the central nervous system and is believed to function as a neurotransmitter as well as a gut hormone with an inverse correlation of its level to anxiety and depression. Therefore, CCK receptors (CCKRs) could be a relevant target for novel antidepressant therapy.

METHODS: In silico target prediction was first employed to predict the probability of the bromophenols interacting with key protein targets based on a model trained on known bioactivity data and chemical similarity considerations. Next, we tested the functional effect of natural bromophenols from Symphyocladia latiuscula on the CCK2 receptor followed by a molecular docking simulation to predict interactions between a compound and the binding site of the target protein.

RESULTS: Results of cell-based functional G-protein coupled receptor (GPCR) assays demonstrate that bromophenols 2,3,6-tribromo-4,5-dihydroxybenzyl alcohol (1), 2,3,6-tribromo-4,5-dihydroxybenzyl methyl ether (2), and bis-(2,3,6-tribromo-4,5-dihydroxybenzyl) ether (3) are full CCK2 antagonists. Molecular docking simulation of 1‒3 with CCK2 demonstrated strong binding by means of interaction with prime interacting residues: Arg356, Asn353, Val349, His376, Phe227, and Pro210. Simulation results predicted good binding scores and interactions with prime residues, such as the reference antagonist YM022.

CONCLUSIONS: The results of this study suggest bromophenols 1-3 are CCK2R antagonists that could be novel therapeutic agents for CCK2R-related diseases, especially anxiety and depression.

* Title and MeSH Headings from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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