Fragment-based discovery of small molecule inhibitors of RAGE

基于片段的 RAGE 小分子抑制剂的发现

基本信息

批准号：
9766812
负责人：
Natalia Kozlyuk
金额：
$ 2.76万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-01 至 2020-02-07
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9766812
关键词：
Advanced Glycosylation End Products Affinity Alzheimer&apos s Disease Amyloid beta-Protein Arthritis Binding Binding Sites Biological Assay Biological Process Biophysics Cell Surface Receptors Cell Survival Cells Chemicals Chronic Collaborations Complex Crystallization Data Diabetes Mellitus Disease Dose Foundations Generations Goals In Vitro Inflammation Inflammatory Inflammatory Response Lead Libraries Ligand Binding Ligand Binding Domain Ligands Link Location Luciferases Metabolic Molecular Monitor Pathway interactions Pattern Recognition Pattern recognition receptor Permeability Pharmaceutical Chemistry Process Publishing Receptor Activation Receptor Inhibition Reporter Research Roentgen Rays S100 Proteins Series Signal Pathway Signal Transduction Site Specificity Structure Structure-Activity Relationship Surface Techniques Testing Therapeutic X-Ray Crystallography activation product associated symptom base design extracellular inhibitor/antagonist molecular modeling programs receptor binding receptor for advanced glycation endproducts screening small molecule small molecule inhibitor therapeutic target

项目摘要

Project Summary The receptor for advanced glycation end products (RAGE) is a multi-ligand pattern recognition cell surface receptor, which upon activation stimulates intracellular inflammatory signaling with implications in diabetes, arthritis, Alzheimer’s and other diseases. The mechanistic understanding of the RAGE signaling axis is poorly understood. Moreover, inhibition of RAGE-ligand interactions represents an attractive potential therapeutic strategy to suppress the symptoms associated with chronic inflammatory processes. This proposal seeks to develop inhibitors of RAGE-ligand interactions to further discern the mechanism of RAGE activation and downstream signaling, as well as to lay the foundation to evaluate the therapeutic potential of inhibiting RAGE to suppress the disease-associated chronic inflammatory processes. Here, we propose to pursue fragment- based molecular discovery based on fragment screening via the Structure Activity Relationship (SAR) by NMR approach. Aim 1 uses SAR by NMR to screen a highly curated library ~ 15,000 fragments. The goal is to identify fragment molecules that bind to different sites within the RAGE-ligand binding interface. The exact location and orientation of the hit fragments will be determined using X-ray crystallography in Aim 2. The crystal structures will then used to elaborate fragments and design linkers between fragments bound to different sites to generate high affinity compounds. In Aim 3, first biophysical and structural techniques will be employed to characterize the specificity of the lead compounds. A selection of the best leads will then be subjected to in vitro cell-based assays to determine the effects on downstream inflammatory signaling.

项目概要晚期糖基化终末产物 (RAGE) 的受体是一种多配体模式识别细胞表面受体，激活后会刺激细胞内炎症信号传导，从而对糖尿病产生影响，人们对 RAGE 信号轴的机制了解甚少。此外，抑制 RAGE-配体相互作用是一种有吸引力的潜在治疗方法。该提案旨在抑制与慢性炎症过程相关的症状。开发 RAGE-配体相互作用的抑制剂，以进一步了解 RAGE 激活的机制和下游信号传导，并为评估抑制 RAGE 的治疗潜力奠定基础抑制与疾病相关的慢性炎症过程。在这里，我们建议追求片段- 基于通过 NMR 构效关系 (SAR) 进行片段筛选的分子发现目标 1 使用 NMR 筛选高度精选的文库，目标是 15,000 个片段。识别与 RAGE 配体结合界面内不同位点结合的片段分子。命中碎片的位置和方向将使用目标 2 中的 X 射线晶体学来确定。然后，晶体结构将用于精制片段并设计片段之间的连接体在目标 3 中，首先是生物物理和结构技术。然后将用于表征先导化合物的特异性。进行体外基于细胞的测定以确定对下游炎症信号传导的影响。