Jackson Graham E, Gäde Gerd, Marco Heather G
Department of Chemistry, University of Cape Town, Cape Town 7701, South Africa.
Department of Biological Sciences, University of Cape Town, Cape Town 7701, South Africa.
Life (Basel). 2022 Mar 7;12(3):387. doi: 10.3390/life12030387.
Adipokinetic hormone (AKH) is one of the most important metabolic neuropeptides in insects, with actions similar to glucagon in vertebrates. AKH regulates carbohydrate and fat metabolism by mobilizing trehalose and diacylglycerol into circulation from glycogen and triacylglycerol stores, respectively, in the fat body. The short peptide (8 to 10 amino acids long) exerts its function by binding to a rhodopsin-like G protein-coupled receptor located in the cell membrane of the fat body. The AKH receptor (AKHR) is, thus, a potential target for the development of novel specific (peptide) mimetics to control pest insects, such as locusts, which are feared for their prolific breeding, swarm-forming behavior and voracious appetite. Previously, we proposed a model of the interaction between the three endogenous AKHs of the desert locust, Schistocerca gregaria, and the cognate AKHR (Jackson et al., Peer J. 7, e7514, 2019). In the current study we have performed in silico screening of two databases (NCI Open 2012 library and Zinc20) to identify compounds which may fit the endogenous Schgr-AKH-II binding site on the AKHR of S. gregaria. In all, 354 compounds were found to fit the binding site with glide scores < −8. Using the glide scores and binding energies, 7 docked compounds were selected for molecular dynamic simulation in a phosphatidylcholine membrane. Of these 7 compounds, 4 had binding energies which would allow them to compete with Schgr-AKH-II for the receptor binding site and so are proposed as agonistic ligand candidates. One of the ligands, ZINC000257251537, was tested in a homospecific in vivo biological assay and found to have significant antagonistic activity.
脂肪动激素（AKH）是昆虫中最重要的代谢神经肽之一，其作用类似于脊椎动物中的胰高血糖素。AKH通过分别将海藻糖和二酰甘油从脂肪体中的糖原和三酰甘油储存库动员到循环中，来调节碳水化合物和脂肪代谢。这种短肽（8至10个氨基酸长）通过与位于脂肪体细胞膜上的视紫红质样G蛋白偶联受体结合来发挥其功能。因此，AKH受体（AKHR）是开发新型特异性（肽）模拟物以控制害虫（如蝗虫）的潜在靶点，蝗虫因其繁殖力强、成群行为和贪婪食欲而令人担忧。此前，我们提出了沙漠蝗虫（Schistocerca gregaria）的三种内源性AKH与同源AKHR之间相互作用的模型（Jackson等人，《Peer J.》7，e7514，2019）。在当前研究中，我们对两个数据库（NCI Open 2012库和Zinc20）进行了虚拟筛选，以鉴定可能适合沙漠蝗虫AKHR上内源性Schgr - AKH - II结合位点的化合物。总共发现354种化合物的滑行分数< -8，符合结合位点。利用滑行分数和结合能，选择了7种对接化合物在磷脂酰胆碱膜中进行分子动力学模拟。在这7种化合物中，有4种的结合能使其能够与Schgr - AKH - II竞争受体结合位点，因此被提议作为激动剂配体候选物。其中一种配体ZINC000257251537在同种体内生物学试验中进行了测试，发现具有显著的拮抗活性。
