Sweden and Science for Life Laboratory, Department of Cell and Molecular Biology, BMC (H.G.T.), Biomedical Centre (BMC), Uppsala University, P.O. BOX 596, SE-751 24 Uppsala, Sweden.
Department of Medicinal Chemistry, Division of Organic Pharmaceutical Chemistry, BMC, Uppsala University, P.O. Box 574, SE-751 23 Uppsala, Sweden.
Biomolecules. 2020 Apr 23;10(4):649. doi: 10.3390/biom10040649.
Angiotensin II receptor type 1 and 2 (AT1R and AT2R) are two G-protein coupled receptors that mediate most biological functions of the octapeptide Angiotensin II (Ang II). AT2R is upregulated upon tissue damage and its activation by selective AT2R agonists has become a promising approach in the search for new classes of pharmaceutical agents. We herein analyzed the chemical evolution of AT2R agonists starting from octapeptides, through shorter peptides and peptidomimetics to the first drug-like AT2R-selective agonist, C21, which is in Phase II clinical trials and aimed for idiopathic pulmonary fibrosis. Based on the recent crystal structures of AT1R and AT2R in complex with sarile, we identified a common binding model for a series of 11 selected AT2R agonists, consisting of peptides and peptidomimetics of different length, affinity towards AT2R and selectivity versus AT1R. Subsequent molecular dynamics simulations and free energy perturbation (FEP) calculations of binding affinities allowed the identification of the bioactive conformation and common pharmacophoric points, responsible for the key interactions with the receptor, which are maintained by the drug-like agonists. The results of this study should be helpful and facilitate the search for improved and even more potent AT2R-selective drug-like agonists.
血管紧张素 II 受体 1 型和 2 型（AT1R 和 AT2R）是两种 G 蛋白偶联受体，介导八肽血管紧张素 II（Ang II）的大多数生物学功能。AT2R 在组织损伤时上调，其被选择性 AT2R 激动剂激活已成为寻找新类别的药物的一种很有前途的方法。我们在此分析了从八肽开始的 AT2R 激动剂的化学进化，经过较短的肽和肽模拟物，到第一个类似药物的 AT2R 选择性激动剂 C21，它正在进行 II 期临床试验，用于特发性肺纤维化。基于最近的 AT1R 和 AT2R 与沙利度胺复合物的晶体结构，我们确定了一系列 11 种选定的 AT2R 激动剂的共同结合模型，这些激动剂包括不同长度、对 AT2R 的亲和力和对 AT1R 的选择性的肽和肽模拟物。随后进行的结合亲和力的分子动力学模拟和自由能扰动（FEP）计算，确定了生物活性构象和共同的药效基团，这些构象和药效基团负责与受体的关键相互作用，这些作用由类似药物的激动剂维持。这项研究的结果应该是有帮助的，并有助于寻找改进的、甚至更有效的 AT2R 选择性类似药物的激动剂。
