Structure-Based Design of Novel HNF4a Antagonists to Treat Metabolic Syndrome

基于结构的新型 HNF4a 拮抗剂治疗代谢综合征的设计

• 批准号: 7801411
• 负责人: ARNOLD T HAGLER
• 金额: $ 29.02万
• 依托单位: SHIFA BIOMEDICAL CORPORATION
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7801411
• 关键词: AF2; Accounting; Acids; Active Sites; Address; Adopted; Adult; Adverse effects; Affect; Age; Agonist; Algorithms; American; Atherosclerosis; Bile Acid Biosynthesis Pathway; Bile Acids; Binding; Binding Sites; Biological; Biological Assay; Blood; Cardiac; Cells; Cessation of life; Characteristics; Charge; Clinical; Combined Modality Therapy; Complex; Computer Simulation; Coronary heart disease; Data; Databases; Development; Diabetes Mellitus; Diet; Disease; Docking; Drug Delivery Systems; Drug Interactions; Dyslipidemias; Energy Metabolism; Ensure; Enzymes; Epidemic; Family; Family member; Fatty acid glycerol esters; Feedback; Free Energy; Generations; Genes; Genetic Transcription; Glucose; Glucose Intolerance; Goals; Heart Diseases; High Density Lipoproteins; Hyperglycemia; Hyperlipidemia; Hypertension; Hypertriglyceridemia; Incidence; Individual; Insulin Resistance; Lead; Ligand Binding; Ligand Binding Domain; Ligands; Link; Lipids; Mediterranean Diet; Metabolic syndrome; Methods; Myocardial Infarction; Non-Insulin-Dependent Diabetes Mellitus; Nuclear Orphan Receptor; Nuclear Receptors; Nucleic Acids; Obesity; Omega-3 Fatty Acids; Pharmaceutical Preparations; Phase; Physiology; Polyunsaturated Fatty Acids; Population; Prevalence; Procedures; Proteins; Quantum Mechanics; Regulation; Reporting; Resistance development; Risk; Risk Factors; Roentgen Rays; Role; Sampling; Saturated Fatty Acids; Screening procedure; Site; Solvents; Stroke; Structure; Syndrome; Techniques; Testing; Therapeutic; Time; Tissues; Training; Transcriptional Activation; Transcriptional Regulation; Work; X-Ray Crystallography; Zinc Compounds; analog; base; blood glucose regulation; blood pressure regulation; design; diabetes risk; diabetic; drug discovery; functional group; glucose-6-phosphatase; hepatocyte nuclear factor; in vitro Assay; meetings; member; molecular dynamics; novel; novel strategies; public health relevance; receptor; receptor binding; response; restraint; simulation; small molecule; success; transcription factor; virtual

DESCRIPTION (provided by applicant): The long-term goal of this work is to develop novel drugs for the treatment of metabolic syndrome (MetS). MetS is an assemblage of associated clinical disorders recognized only some 20 years ago to be linked. They include insulin resistance, hypertension, dyslipidemia (i.e. hypertriglyceridemia and low HDL levels), glucose intolerance, and obesity. The incidence of MetS has reached epidemic proportions afflicting ~64 million Americans and significantly increasing the risk of coronary heart disease (CHD), atherosclerosis, diabetes, myocardial infarction, stroke and even death in those afflicted. At this time there are no drugs available for the treatment of MetS per se. Although drugs do exist for the individual components, complications due to drug interactions, side effects, and the sheer number of drugs that are needed, along with the serious consequences of the disease, make the development of a new approach urgent. To address this need, we will adopt a novel approach to the problem, designing antagonists that target the nuclear receptor HNF4a. HNF4a is a transcription factor involved in lipid and glucose homeostasis and the transcriptional regulation of genes involved in energy metabolism, as well as blood pressure homeostasis. Thus, it is involved in regulation of all components of MetS, and a growing body of biological data supports its role in the treatment of the multiple components of MetS. Current drugs that target antagonizing nuclear receptors bind to the ligand-binding site (LBS) where they alter the dynamics and structure of the receptor, resulting in an inability of necessary coactivators to bind to the coactivator-binding site (AF-2) thus interfering with transcription. Rather than focusing solely on the LBS, we will exploit the unusual multiplicity of sites in a single drug target (AF-2 and LBS) to carry out a, two-site, drug discovery strategy that leverages both experimental and theoretical efforts and provides new mechanistic approaches to overcoming MetS. To this end we will integrate in silico induced-fit docking with cell based transcription assays, X-ray crystallography, and molecular dynamics free energy pertubation and replica exchange simulations to find confirmed hits (X-ray and assays) and determine structural design criteria for lead optimization of compounds at these sites. PUBLIC HEALTH RELEVANCE: Metabolic syndrome (MetS) is an assemblage of associated clinical disorders that includes insulin resistance, hypertension, dyslipidemia (i.e. hypertriglyceridemia and low HDL levels), glucose intolerance, and obesity. The incidence of MetS has reached epidemic proportions afflicting ~64 million Americans and significantly increasing the risk of coronary heart disease, atherosclerosis, diabetes, myocardial infarction, stroke and even death in those afflicted. To develop a drug to address this complex disease, we will take a novel approach, designing compounds that target the nuclear receptor HNF4a, which is involved in regulating all components of this syndrome.

描述（由申请人提供）：这项工作的长期目标是开发用于治疗代谢综合征（MetS）的新药。代谢综合征是20年前才认识到的相关临床疾病的集合。它们包括胰岛素抵抗、高血压、血脂异常（即高胆固醇血症和低HDL水平）、葡萄糖耐受不良和肥胖症。MetS的发病率已经达到流行病的比例，影响到约6400万美国人，并显著增加了冠心病（CHD）、动脉粥样硬化、糖尿病、心肌梗死、中风甚至死亡的风险。目前还没有药物可用于治疗MetS本身。虽然药物确实存在于单个成分中，但由于药物相互作用，副作用和所需药物的绝对数量沿着疾病的严重后果而导致的并发症使得迫切需要开发新方法。为了满足这一需求，我们将采用一种新的方法来解决这个问题，设计靶向核受体HNF 4a的拮抗剂。HNF 4a是一种参与脂质和葡萄糖稳态以及参与能量代谢和血压稳态的基因的转录调节的转录因子。因此，它参与调节代谢综合征的所有组成部分，越来越多的生物学数据支持它在治疗代谢综合征的多个组成部分中的作用。目前靶向拮抗性核受体的药物结合到配体结合位点（LBS），在那里它们改变受体的动力学和结构，导致必需的辅激活因子不能结合到辅激活因子结合位点（AF-2），从而干扰转录。而不是只专注于LBS，我们将利用一个单一的药物靶点（AF-2和LBS）的位点的不寻常的多样性，进行一个，两个网站，药物发现策略，利用实验和理论的努力，并提供新的机制方法来克服代谢综合征。为此，我们将在计算机上集成诱导适合对接与基于细胞的转录测定，X射线晶体学，分子动力学自由能扰动和复制交换模拟，以找到确认的命中（X射线和测定），并确定在这些网站的化合物的铅优化的结构设计标准。 公共卫生相关性：代谢综合征（MetS）是相关临床病症的集合，其包括胰岛素抵抗、高血压、血脂异常（即高胆固醇血症和低HDL水平）、葡萄糖耐受不良和肥胖。MetS的发病率已经达到流行病的比例，影响到约6400万美国人，并显著增加了冠心病、动脉粥样硬化、糖尿病、心肌梗死、中风甚至死亡的风险。为了开发一种药物来解决这种复杂的疾病，我们将采取一种新的方法，设计靶向核受体HNF 4a的化合物，HNF 4a参与调节这种综合征的所有成分。