A novel small positive allosteric modulator of neuropeptide receptor PAC1-R exerts neuroprotective effects in MPTP mouse Parkinson's disease model  

作　　者：Guangchun Fan Shang Chen Zhengxin Tao Huahua Zhang Rongjie Yu 

机构地区：[1]Department of Cell Biology,College of Life Science and Technology,Jinan University,Guangzhou 510630,China [2]Guangdong Province Key Laboratory of Bioengineering Medicine,Guangzhou 510630,China [3]Guangdong Provincial Biotechnology Drug&Engineering Technology Research Center,Guangzhou 510630,China [4]National Engineering Research Center of Genetic Medicine,Guangzhou 510630,China [5]Department of Medical Genetics,Guangdong Medical University,Dongguan 523000,China

出　　处：《Acta Biochimica et Biophysica Sinica》2022年第9期1349-1364,共16页生物化学与生物物理学报（英文版）

基　　金：the grants from the National Natural Science Foundation of China(Nos.31100545 and 31670848);the Natural Science Foundation of Guangdong Province(Nos.2016A030313087 and 2022A1515011158).

摘　　要：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.

关 键 词：positive allosteric modulator PACAP receptor 1 DOXYCYCLINE computer virtual screening neuroprotective activity Parkinson's disease 

分 类 号：R285.5[医药卫生—中药学] R742.5[医药卫生—中医学]