Faculty of Chemistry, University of Warsaw, 02-093 Warsaw, Poland.
Institut de Recherche Interdisciplinaire en Biologie Humaine et Moléculaire (IRIBHM), Université libre de Bruxelles, B-1070 Brussels, Belgium.
Int J Mol Sci. 2019 Sep 5;20(18):4348. doi: 10.3390/ijms20184348.
Vasoactive intestinal peptide receptor 1 (VPAC1) is a member of a secretin-like subfamily of G protein-coupled receptors. Its endogenous neuropeptide (VIP), secreted by neurons and immune cells, modulates various physiological functions such as exocrine and endocrine secretions, immune response, smooth muscles relaxation, vasodilation, and fetal development. As a drug target, VPAC1 has been selected for therapy of inflammatory diseases but drug discovery is still hampered by lack of its crystal structure. In this study we presented the homology model of this receptor constructed with the well-known web service GPCRM. The VPAC1 model is composed of extracellular and transmembrane domains that form a complex with an endogenous hormone VIP. Using the homology model of VPAC1 the mechanism of action of potential drug candidates for VPAC1 was described. Only two series of small-molecule antagonists of confirmed biological activity for VPAC1 have been described thus far. Molecular docking and a series of molecular dynamics simulations were performed to elucidate their binding to VPAC1 and resulting antagonist effect. The presented work provides the basis for the possible binding mode of VPAC1 antagonists and determinants of their molecular recognition in the context of other class B GPCRs. Until the crystal structure of VPAC1 will be released, the presented homology model of VPAC1 can serve as a scaffold for drug discovery studies and is available from the author upon request.
血管活性肠肽受体 1（VPAC1）是 G 蛋白偶联受体家族中分泌素样亚家族的成员。其内源性神经肽（VIP）由神经元和免疫细胞分泌，调节各种生理功能，如外分泌和内分泌分泌、免疫反应、平滑肌松弛、血管扩张和胎儿发育。作为一种药物靶点，VPAC1 已被选为治疗炎症性疾病的药物，但由于缺乏其晶体结构，药物发现仍然受到阻碍。在这项研究中，我们使用著名的网络服务 GPCRM 构建了该受体的同源模型。VPAC1 模型由细胞外和跨膜结构域组成，这些结构域与内源性激素 VIP 形成复合物。使用 VPAC1 的同源模型，描述了潜在药物候选物对 VPAC1 的作用机制。迄今为止，仅描述了两种具有明确生物学活性的 VPAC1 小分子拮抗剂系列。进行了分子对接和一系列分子动力学模拟，以阐明它们与 VPAC1 的结合及其产生的拮抗剂作用。所提出的工作为 VPAC1 拮抗剂的可能结合模式及其在其他 B 类 GPCR 中的分子识别决定因素提供了依据。在 VPAC1 的晶体结构发布之前，所提出的 VPAC1 同源模型可以作为药物发现研究的支架，并可根据要求向作者索取。
