Investigation and Targeting of Alternate Binding Site in ERRα

ERRα 中替代结合位点的调查和靶向

基本信息

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
项目类别：
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

项目摘要

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.

抽象的世界卫生组织宣布糖尿病患者人数显着增加，从 108 人增加到 108 人。 1980 年的 100 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造成 150 万人死亡因此，人们对确定新的药物靶点和替代药物越来越感兴趣。雌激素相关受体 α (ERRα) 是一种核激素受体。调节与抗炎活性、氧化磷酸化相关的基因表达，大量数据表明 ERRα 是一种有前途的治疗方法。治疗代谢紊乱的目标，例如2型糖尿病和代谢综合征。 ERRα选择性小分子激动剂的鉴定将是有价值的化学探针药理学工具进一步探讨ERRα在糖尿病中的作用然而，现有的ERRα。激动剂缺乏用作化学探针所需的体内效力和选择性。此外，没有可用于 ERRα 结合激动剂的 X 射线晶体结构，这阻碍了特定 ERRα 激动剂的发现。了解激动剂配体的分子基础。与 ERRα 的结合对于新型强效特异性激动剂的鉴定和优化至关重要。使用分子动力学模拟进行的初步初步研究揭示了新颖的存在 ERRα 中的替代结合位点是发现新发现的前提。我们建议分两个阶段完成两个具体目标：1）研究激动剂配体与 ERRα 正构和变构位点结合的机制计算和实验方法对于表征低能态至关重要。有利于激动剂与 ERRα 结合的结构整体 2) 基于计算机的药物的实施。设计方法，例如用于发现新分子的基于结构的虚拟筛选结合并选择性激活 ERRα 的支架这些目标将提供新颖的、一流的配体。选择性激活 ERRα，可用作化学探针来研究其在糖尿病在未来的拨款提案中。