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.
Acta Biochim Biophys Sin (Shanghai). 2022 Sep 25;54(9):1349-1364. doi: 10.3724/abbs.2022126.
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.
作为一种神经肽垂体腺苷酸环化酶激活肽（PACAP）优先受体，PAC1-R 介导有效的神经保护活性。基于具有临床神经保护活性的抗生素强力霉素（DOX）作为神经肽 PACAP 受体 1（PAC1-R）的正变构调节剂（PAM）的发现，我们使用虚拟和实验室筛选来寻找新型小分子 PAC1-R 的 PAMs。虚拟筛选使用小分子库 TargetMol 进行。经过 Glide 的两级精度筛选，选择并命名了 top5 种与 PAC1-R 具有最佳预测亲和力的化合物，分别为小分子正变构调节剂 1-5（SPAM1-5）。我们的结果表明，只有 4-[[4-(4-氧代-3,4-二氢-2H-吡喃-2-基)丁酰胺基]甲基]苯甲酸（SPAM1）在 MPP+PD 细胞模型和 MPTP PD 小鼠模型中比 DOX 具有更强的神经保护活性。SPAM1 对 PAC1-R 的亲和力高于 DOX，但没有抗生素活性。此外，SPAM1 和 DOX 均可阻止 MPTP 诱导的小鼠脑组织中 PAC1-R 水平下降。SPAM1 的成功筛选为靶向 PAC1-R 的神经退行性疾病治疗提供了一种新型药物。
