A novel small positive allosteric modulator of neuropeptide receptor PAC1-R exerts neuroprotective effects in MPTP mouse Parkinson’s disease model
As a neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP)-preferring receptor, PAC1-R mediates effective neuroprotective activity. Based on the finding that the antibiotic doxycycline (DOX) with clinical neuroprotective activity functions as a positive allosteric modulator (PAM) o...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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China Science Publishing & Media Ltd.
2022-09-01
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| Series: | Acta Biochimica et Biophysica Sinica |
| Subjects: | |
| Online Access: | https://www.sciengine.com/doi/10.3724/abbs.2022126 |
| _version_ | 1797635352669716480 |
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| author | Fan Guangchun Chen Shang Tao Zhengxin Zhang Huahua Yu Rongjie |
| author_facet | Fan Guangchun Chen Shang Tao Zhengxin Zhang Huahua Yu Rongjie |
| author_sort | Fan Guangchun |
| collection | DOAJ |
| description | As a neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP)-preferring receptor, PAC1-R mediates effective neuroprotective activity. Based on the finding that the antibiotic doxycycline (DOX) with clinical neuroprotective activity functions as a positive allosteric modulator (PAM) of neuropeptide PACAP receptor 1 (PAC1-R), we use virtual and laboratory screening to search for novel small molecule PAMs of PAC1-R. Virtual screening is carried out using a small-molecule library TargetMol. After two-level precision screening with Glide, the top five compounds with the best predicted affinities for PAC1-R are selected and named small positive allosteric modulator 1‒5 (SPAM1‒5). Our results show that only 4-{[4-(4-Oxo-3,4-2-yl)butanamido]methyl}benzoic acid (SPAM1) has stronger neuroprotective activity than DOX in the MPP+ PD cell model and MPTP PD mouse model. SPAM1 has a higher affinity for PAC1-R than DOX, but has no antibiotic activity. Moreover, both SPAM1 and DOX block the decrease of PAC1-R level in mouse brain tissues induced by MPTP. The successful screening of SPAM1 offers a novel drug for the treatment of neurodegenerative disease targeting the PAC1-R. |
| first_indexed | 2024-03-11T12:20:59Z |
| format | Article |
| id | doaj.art-9dae328967da4a06b8658dbdef6e651f |
| institution | Directory Open Access Journal |
| issn | 1672-9145 |
| language | English |
| last_indexed | 2024-03-11T12:20:59Z |
| publishDate | 2022-09-01 |
| publisher | China Science Publishing & Media Ltd. |
| record_format | Article |
| series | Acta Biochimica et Biophysica Sinica |
| spelling | doaj.art-9dae328967da4a06b8658dbdef6e651f2023-11-07T01:01:40ZengChina Science Publishing & Media Ltd.Acta Biochimica et Biophysica Sinica1672-91452022-09-01541349136410.3724/abbs.202212620d259ccA novel small positive allosteric modulator of neuropeptide receptor PAC1-R exerts neuroprotective effects in MPTP mouse Parkinson’s disease modelFan Guangchun0Chen Shang1Tao Zhengxin2Zhang Huahua3Yu Rongjie4["Department of Cell Biology, College of Life Science and Technology, Jinan University, Guangzhou 510630, China"]["Department of Cell Biology, College of Life Science and Technology, Jinan University, Guangzhou 510630, China"]["Department of Cell Biology, College of Life Science and Technology, Jinan University, Guangzhou 510630, China"]["Department of Medical Genetics, Guangdong Medical University, Dongguan 523000, China"]["Department of Cell Biology, College of Life Science and Technology, Jinan University, Guangzhou 510630, China","Guangdong Province Key Laboratory of Bioengineering Medicine, Guangzhou 510630, China","Guangdong Provincial Biotechnology Drug & Engineering Technology Research Center, Guangzhou 510630, China","National Engineering Research Center of Genetic Medicine, Guangzhou 510630, China"]As a neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP)-preferring receptor, PAC1-R mediates effective neuroprotective activity. Based on the finding that the antibiotic doxycycline (DOX) with clinical neuroprotective activity functions as a positive allosteric modulator (PAM) of neuropeptide PACAP receptor 1 (PAC1-R), we use virtual and laboratory screening to search for novel small molecule PAMs of PAC1-R. Virtual screening is carried out using a small-molecule library TargetMol. After two-level precision screening with Glide, the top five compounds with the best predicted affinities for PAC1-R are selected and named small positive allosteric modulator 1‒5 (SPAM1‒5). Our results show that only 4-{[4-(4-Oxo-3,4-2-yl)butanamido]methyl}benzoic acid (SPAM1) has stronger neuroprotective activity than DOX in the MPP+ PD cell model and MPTP PD mouse model. SPAM1 has a higher affinity for PAC1-R than DOX, but has no antibiotic activity. Moreover, both SPAM1 and DOX block the decrease of PAC1-R level in mouse brain tissues induced by MPTP. The successful screening of SPAM1 offers a novel drug for the treatment of neurodegenerative disease targeting the PAC1-R.https://www.sciengine.com/doi/10.3724/abbs.2022126positive allosteric modulatorPACAP receptor 1doxycyclinecomputer virtual screeningneuroprotective activityParkinson’s disease |
| spellingShingle | Fan Guangchun Chen Shang Tao Zhengxin Zhang Huahua Yu Rongjie A novel small positive allosteric modulator of neuropeptide receptor PAC1-R exerts neuroprotective effects in MPTP mouse Parkinson’s disease model Acta Biochimica et Biophysica Sinica positive allosteric modulator PACAP receptor 1 doxycycline computer virtual screening neuroprotective activity Parkinson’s disease |
| title | A novel small positive allosteric modulator of neuropeptide receptor PAC1-R exerts neuroprotective effects in MPTP mouse Parkinson’s disease model |
| title_full | A novel small positive allosteric modulator of neuropeptide receptor PAC1-R exerts neuroprotective effects in MPTP mouse Parkinson’s disease model |
| title_fullStr | A novel small positive allosteric modulator of neuropeptide receptor PAC1-R exerts neuroprotective effects in MPTP mouse Parkinson’s disease model |
| title_full_unstemmed | A novel small positive allosteric modulator of neuropeptide receptor PAC1-R exerts neuroprotective effects in MPTP mouse Parkinson’s disease model |
| title_short | A novel small positive allosteric modulator of neuropeptide receptor PAC1-R exerts neuroprotective effects in MPTP mouse Parkinson’s disease model |
| title_sort | novel small positive allosteric modulator of neuropeptide receptor pac1 r exerts neuroprotective effects in mptp mouse parkinson s disease model |
| topic | positive allosteric modulator PACAP receptor 1 doxycycline computer virtual screening neuroprotective activity Parkinson’s disease |
| url | https://www.sciengine.com/doi/10.3724/abbs.2022126 |
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