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Rational Drug Design for Chronic Neuronal Damage

针对慢性神经元损伤的合理药物设计

基本信息

批准号：
9550891
负责人：
Steffen Lindert
金额：
$ 7.8万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-01 至 2020-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9550891
关键词：
Ablation Agonist Algorithms Alzheimer&apos s Disease Animal Model Animal Testing Binding Binding Sites Biochemical Biological Assay Biophysics CCNA2 gene Cell Cycle Cell Survival Cell physiology Cells Central Nervous System Diseases Chronic Clinical Collaborations Complex Computer Assisted Computing Methodologies Cyclin-Dependent Kinases DNA DNA Damage DNA Double Strand Break DNA Repair DNA Repair Pathway Data Databases Development Discipline Disease Double Strand Break Repair Drug Binding Site Drug Design Drug effect disorder Exhibits Experimental Models Failure Foundations Functional disorder Genome Genome Stability Genomic DNA Goals Homeostasis In Vitro Interdisciplinary Study Intervention Joints Knowledge Lead Learning Lobe Memory impairment Metabolic Methods Mission Molecular Conformation Names Nerve Degeneration Neurodegenerative Disorders Neurons Pathology Pathway interactions Patients Pharmaceutical Preparations Pharmacology Pilot Projects Preclinical Testing Protein Dynamics Proteins Public Health Reactive Oxygen Species Reporting Research Research Design Resolution Role Sampling Scheme Structure Temporal Lobe Testing Time United States National Institutes of Health Work base college computational chemistry computer studies cyclin A2 expectation experience flexibility human disease improved in vitro activity in vivo molecular dynamics novel pre-clinical protein structure receptor repaired screening small molecule therapeutic target tool virtual

项目摘要

Project Summary / Abstract DNA repair is a set of important cellular processes which identify and restore damage to the cellular DNA molecules encoding the genome. Failure of proper DNA repair is associated with many forms of disease, among them neurodegenerative disorders such as Alzheimer's disease. Since neurons are constantly cycling cells, their metabolic demand is much higher when compared to normal non-cycling cells. As a result of this, they build up a high number of reactive oxygen species which tend to cause DNA damage. Patients with neurodegenerative disorders often exhibit elevated levels of DNA damage. Thus one possible intervention could be activated DNA repair, however no clinically approved drugs are available for this purpose. In previous research we found that the neuronal protein cyclin A2 is a regulator of neuronal genomic stability and DNA repair, while inhibition of cyclin A2 leads to learning and memory deficits in test animals. The structure of cyclin A2 is known but no small molecule binders have been reported. The main objective of this proposal is to use computational methods to find a set of small molecules that bind to cyclin A2 and can act as activators (agonists). We will use biochemical methods to verify our computational predictions. The proposed research is structured into two main stages. First, we will thoroughly sample the dynamics of the cyclin A2 protein and identify potential drug binding sites (Aim I). Subsequently, we will perform a structure-based computational screening of large virtual compound databases to identify potential cyclin A2 agonists, whose activity will be verified using in vitro biochemical and cell-based assays (Aim II). The proposed research combines aspects of computational chemistry, biophysics and pharmacology.

项目摘要/摘要 DNA修复是一系列重要的细胞过程，它识别和修复细胞的损伤编码基因组的细胞DNA分子。正确的DNA修复失败与许多形式的疾病，其中包括神经退行性疾病，如阿尔茨海默病。由于神经元不断地对细胞进行循环，它们的新陈代谢需求要高得多变成正常的非周期细胞。结果是，它们形成了大量的活性氧。容易造成DNA损伤的物种。神经退行性疾病的患者通常表现为 DNA损伤水平升高。因此，一种可能的干预措施是激活DNA修复，然而，目前还没有临床批准的药物可用于这一目的。在之前的研究中，我们发现神经元蛋白Cyclin A2是神经元基因组稳定性和DNA修复的调节器，而抑制细胞周期蛋白A2则会导致实验动物的学习和记忆障碍。的结构细胞周期蛋白A2是已知的，但还没有小分子结合蛋白的报道。这项工作的主要目标是一项提议是使用计算方法找到一组与细胞周期蛋白A2可作为激活剂(激动剂)。我们将使用生化方法来验证我们的计算预测。拟议的研究分为两个主要阶段。第一, 我们将彻底采样周期蛋白A2的动态，并确定潜在的药物结合地点(目标I)。随后，我们将执行基于结构的大型计算筛选虚拟化合物数据库，以确定潜在的细胞周期蛋白A2激动剂，其活性将得到验证使用体外生化和细胞分析(AIM II)。拟议的研究结合了计算化学、生物物理学和药理学方面。