Investigation and Targeting of Alternate Binding Site in ERRα

ERRα 中替代结合位点的调查和靶向

• 批准号: 10432870
• 负责人: Lamees Hegazy
• 金额: $ 19.39万
• 依托单位: ST. LOUIS COLLEGE OF PHARMACY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10432870
• 关键词: Agonist; Allosteric Site; Anti-Inflammatory Agents; Applications Grants; Binding; Binding Sites; Biogenesis; Biological Assay; Blindness; Cells; Cessation of life; Characteristics; Chemicals; Collaborations; Complex; Computers; Crystallization; Data; Diabetes Mellitus; Docking; Drug Design; Foundations; Free Energy; Future; Gene Expression; Investigation; Ligand Binding; Ligands; Lower Extremity; Metabolic Diseases; Metabolic syndrome; Methods; Molecular; Molecular Conformation; Mutagenesis; Myocardial Infarction; Non-Insulin-Dependent Diabetes Mellitus; Nuclear Hormone Receptors; Oxidative Phosphorylation; Patients; Pharmaceutical Preparations; Pharmacology; Phase; Property; Protein Isoforms; Proteins; Radio; Receptor Activation; Reporting; Research Project Grants; Resolution; Roentgen Rays; Role; Shapes; Signal Transduction; Site; Structure; Surface; Therapeutic; Transfection; Validation; Work; World Health Organization; base; computer studies; design; estrogen-related receptor; experimental group; fatty acid metabolism; in vivo; insight; interest; limb amputation; molecular dynamics; molecular modeling; new therapeutic target; novel; rational design; scaffold; simulation; small molecule; small molecule libraries; therapeutic target; tool; virtual; virtual screening

Abstract The World Health Organization announced a marked increase in patients with diabetes; from 108 million in 1980 to 422 million in 2014. Diabetes causes severe complications including blindness, heart attacks and lower limb amputation with an estimated 1.5 million deaths annually caused by diabetes. Therefore, there is growing interest in identifying novel drug targets and alternative therapeutics approaches. Estrogen-related receptor α (ERRα) is a nuclear hormone receptor that regulate gene expressions related to anti-inflammatory activities, oxidative phosphorylation, biogenesis and fatty acid metabolism. Large body of data suggest ERRα as a promising therapeutic target in treating metabolic disorders, such as type 2 diabetes and metabolic syndrome. The identification of ERRα selective small molecule agonists would be valuable chemical probes and pharmacological tools to further explore the role of ERRα in diabetes. However, existing ERRα agonists lack in vivo potency and selectivity that are required for their use as chemical probes. In addition, there are no X-ray crystal structures available for ERRα bound agonists, which hindered the discovery of specific ERRα agonists. Understanding the molecular basis of agonist ligand binding to ERRα is crucial for identification and optimization of novel potent and specific agonists. Initial preliminary studies using molecular dynamics simulations, revealed the presence of novel alternate binding site in ERRα. Targeting this alternate site holds premise for discovery of novel ERRα agonists. We propose two specific aims to be done in two phases: 1) Investigation of the mechanism of agonist ligand binding to ERRα orthosteric and allosteric sites using a combination of computational and experimental approaches. This step is essential to characterize low energy state structural ensembles favouring agonist binding to ERRα. 2) Implementation of computer-based drug design approaches such as structure-based virtual screening for discovery of new molecular scaffolds that bind and selectively activate ERRα. These aims will provide novel, first in class ligands that selectively activate ERRα and can be used as chemical probes for investigation of their role in diabetes in future grant proposals.

摘要 世界卫生组织宣布糖尿病患者显著增加；从108人 从1980年的4.22亿增加到2014年的4.22亿。糖尿病会导致严重的并发症，包括失明， 心脏病发作和下肢截肢，估计每年有150万人死于 糖尿病。因此，人们对确定新的药物靶点和替代药物越来越感兴趣 治疗学的方法。雌激素相关受体α(ERRα)是一种核激素受体， 调节与抗炎活性、氧化磷酸化、 生物发生和脂肪酸代谢。大量数据表明Errα是一种有前途的治疗方法 目标是治疗代谢紊乱，如2型糖尿病和代谢综合征。这个 ERRα选择性小分子激动剂的鉴定将是有价值的化学探针和 进一步探讨ERRα在糖尿病中的作用的药理学工具。然而，现有的ERRα 激动剂缺乏作为化学探针所需的体内效力和选择性。在……里面 此外，对于ERRα结合激动剂，没有可用的X射线晶体结构，这阻碍了 发现特定的ERRα激动剂。了解激动剂配体的分子基础 与ERRα的结合对于鉴定和优化新的有效和特定的激动剂至关重要。 使用分子动力学模拟的初步研究揭示了新的 ERRα中的替代结合位点。锁定这个备用地点为发现小说提供了前提 ERRα激动剂。我们建议分两个阶段完成两个具体目标：1)调查 激动剂配体与ERR-α正构和变构结合的机制 计算方法和实验方法。这一步骤对于表征低能量状态是必不可少的 有利于激动剂与ERRα结合的结构系综。2)实现药品电算化 基于结构的虚拟筛选等设计方法用于新分子的发现 结合并选择性激活ERRα的支架。这些目标将提供新颖的、一流的配体 选择性地激活ERRα，并可用作化学探针以研究其在 糖尿病在未来的拨款提案中。