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

描述(由申请人提供)：这项工作的长期目标是开发治疗代谢综合征(METS)的新药。METS是一组相关的临床疾病，大约20年前才被认为是有联系的。这些疾病包括胰岛素抵抗、高血压、血脂异常(即高甘油三酯血症和低高密度脂蛋白水平)、糖耐量异常和肥胖。甲型肝炎的发病率已经达到了流行病的程度，困扰着数百万美国人，并显著增加了患者患冠心病、动脉粥样硬化、糖尿病、心肌梗死、中风甚至死亡的风险。目前还没有治疗甲型肝炎的药物。虽然确实存在针对单个成分的药物，但药物相互作用引起的并发症、副作用、所需药物的绝对数量以及疾病的严重后果，使得开发一种新的方法变得迫切。为了解决这一需求，我们将采用一种新的方法来解决这个问题，设计针对核受体HNF4a的拮抗剂。HNF4a是一种转录因子，参与脂肪和葡萄糖的稳态，以及参与能量代谢和血压稳态的基因的转录调控。因此，它参与了对蛋氨酸的所有成分的调节，越来越多的生物学数据支持它在治疗蛋氨酸的多种成分方面的作用。目前针对拮抗核受体的药物结合到配体结合部位(LBS)，在那里它们改变了受体的动力学和结构，导致必要的辅助激活物无法结合到辅助激活物结合部位(AF-2)，从而干扰转录。与其只关注LBS，我们将利用单一药物靶点(AF-2和LBS)中不同寻常的多样性位点来执行两个位点的药物发现战略，该战略利用实验和理论努力，并提供新的机械方法来克服MET。为此，我们将与基于细胞的转录分析、X射线结晶学、分子动力学自由能微扰和复制交换模拟相结合，以找到已确认的命中结果(X射线和分析)，并确定结构设计标准，以便在这些位置进行化合物的先导优化。 公共卫生相关性：代谢综合征(METS)是一组相关的临床疾病，包括胰岛素抵抗、高血压、血脂异常(即高甘油三酯血症和低高密度脂蛋白水平)、糖耐量异常和肥胖。甲型肝炎的发病率已经达到了流行病的程度，困扰着数百万美国人，并显著增加了患者患冠心病、动脉粥样硬化、糖尿病、心肌梗死、中风甚至死亡的风险。为了开发一种治疗这种复杂疾病的药物，我们将采取一种新的方法，设计针对核受体HNF4a的化合物，HNF4a参与调节这种综合征的所有组成部分。

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.