Bromophenols from Symphyocladia latiuscula (Harvey) Yamada as Novel Cholecystokinin 2 Receptor Antagonists
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 tar...
| Main Authors: | , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
IMR Press
2023-01-01
|
| Series: | Journal of Integrative Neuroscience |
| Subjects: | |
| Online Access: | https://www.imrpress.com/journal/JIN/22/1/10.31083/j.jin2201010 |
| _version_ | 1797937706176610304 |
|---|---|
| author | Pradeep Paudel Se Eun Park Su Hui Seong Fazlin Mohd Fauzi Hyun Ah Jung Jae Sue Choi |
| author_facet | Pradeep Paudel Se Eun Park Su Hui Seong Fazlin Mohd Fauzi Hyun Ah Jung Jae Sue Choi |
| author_sort | Pradeep Paudel |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-10T18:49:33Z |
| format | Article |
| id | doaj.art-abfd98517cf445d7b8a54c54cac33170 |
| institution | Directory Open Access Journal |
| issn | 0219-6352 |
| language | English |
| last_indexed | 2024-04-10T18:49:33Z |
| publishDate | 2023-01-01 |
| publisher | IMR Press |
| record_format | Article |
| series | Journal of Integrative Neuroscience |
| spelling | doaj.art-abfd98517cf445d7b8a54c54cac331702023-02-01T08:23:27ZengIMR PressJournal of Integrative Neuroscience0219-63522023-01-012211010.31083/j.jin2201010S0219-6352(22)00449-1Bromophenols from Symphyocladia latiuscula (Harvey) Yamada as Novel Cholecystokinin 2 Receptor AntagonistsPradeep Paudel0Se Eun Park1Su Hui Seong2Fazlin Mohd Fauzi3Hyun Ah Jung4Jae Sue Choi5Department of Food and Life Science, Pukyong National University, 48513 Busan, Republic of KoreaDepartment of Food and Life Science, Pukyong National University, 48513 Busan, Republic of KoreaDepartment of Food and Life Science, Pukyong National University, 48513 Busan, Republic of KoreaDepartment of Pharmacology and Chemistry, Faculty of Pharmacy, Universiti Teknologi MARA, 42300 Bandar Puncak Alam, Selangor, MalaysiaDepartment of Food Science and Human Nutrition, Jeonbuk National University, 54896 Jeonju, Republic of KoreaDepartment of Food and Life Science, Pukyong National University, 48513 Busan, Republic of KoreaBackground: 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.https://www.imrpress.com/journal/JIN/22/1/10.31083/j.jin2201010bromophenolssymphyocladia latiusculacholecystokinin receptorgpcrsanxietydepression |
| spellingShingle | Pradeep Paudel Se Eun Park Su Hui Seong Fazlin Mohd Fauzi Hyun Ah Jung Jae Sue Choi Bromophenols from Symphyocladia latiuscula (Harvey) Yamada as Novel Cholecystokinin 2 Receptor Antagonists Journal of Integrative Neuroscience bromophenols symphyocladia latiuscula cholecystokinin receptor gpcrs anxiety depression |
| title | Bromophenols from Symphyocladia latiuscula (Harvey) Yamada as Novel Cholecystokinin 2 Receptor Antagonists |
| title_full | Bromophenols from Symphyocladia latiuscula (Harvey) Yamada as Novel Cholecystokinin 2 Receptor Antagonists |
| title_fullStr | Bromophenols from Symphyocladia latiuscula (Harvey) Yamada as Novel Cholecystokinin 2 Receptor Antagonists |
| title_full_unstemmed | Bromophenols from Symphyocladia latiuscula (Harvey) Yamada as Novel Cholecystokinin 2 Receptor Antagonists |
| title_short | Bromophenols from Symphyocladia latiuscula (Harvey) Yamada as Novel Cholecystokinin 2 Receptor Antagonists |
| title_sort | bromophenols from symphyocladia latiuscula harvey yamada as novel cholecystokinin 2 receptor antagonists |
| topic | bromophenols symphyocladia latiuscula cholecystokinin receptor gpcrs anxiety depression |
| url | https://www.imrpress.com/journal/JIN/22/1/10.31083/j.jin2201010 |
| work_keys_str_mv | AT pradeeppaudel bromophenolsfromsymphyocladialatiusculaharveyyamadaasnovelcholecystokinin2receptorantagonists AT seeunpark bromophenolsfromsymphyocladialatiusculaharveyyamadaasnovelcholecystokinin2receptorantagonists AT suhuiseong bromophenolsfromsymphyocladialatiusculaharveyyamadaasnovelcholecystokinin2receptorantagonists AT fazlinmohdfauzi bromophenolsfromsymphyocladialatiusculaharveyyamadaasnovelcholecystokinin2receptorantagonists AT hyunahjung bromophenolsfromsymphyocladialatiusculaharveyyamadaasnovelcholecystokinin2receptorantagonists AT jaesuechoi bromophenolsfromsymphyocladialatiusculaharveyyamadaasnovelcholecystokinin2receptorantagonists |