In Silico Drug Design Targeting RNA Repeat Expansions

针对 RNA 重复扩增的计算机药物设计

基本信息

批准号：
10439166
负责人：
Ilyas Yildirim
金额：
$ 41.95万
依托单位：
FLORIDA ATLANTIC UNIVERSITY
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/10439166
关键词：
Achievement Affinity Algorithms Base Pairing Behavior Binding Biological Process CAG repeat CUG repeat Catalysis Cells Chemistry Code Collaborations Complex Computing Methodologies Development Discipline Disease Docking Drug Design Drug Targeting Elements Environment Florida Fragile X Syndrome Frontotemporal Dementia Gene Expression Genetic Diseases Goals Heritability Huntington Disease Jupiter Lead Ligands Methods Molecular Chaperones Molecular Conformation Myotonic Dystrophy Myotonic dystrophy type 1 Nature Neurosciences Nucleic Acids Pharmaceutical Preparations Pharmacology Pharmacotherapy Physics Pilot Projects Process Property Proteins RNA RNA Binding RNA-Induced Silencing Complex Research Research Institute Research Personnel Series Specificity Structure Students Symptoms Therapeutic Training Transcript Translating Untranslated RNA Vertebral column Work base career development computer science computerized tools design drug development experience functional group gain of function graduate student human disease improved in silico lead optimization novel preference protein folding protein structure rational design responsible research conduct small molecule targeted treatment tool undergraduate student

项目摘要

Project Summary. RNA orchestrates how critical biological functions are controlled, including catalysis, gene expression, enzymatic activities, and protein folding. Misregulation of gene expression cause dysregulation of RNA, which cause many heritable diseases such as Myotonic Dystrophy, Huntington's disease, and Fragile X Syndrome caused by RNA transcripts that contain expanded repeats. The proposal seeks to create unique computational tools to investigate interaction of small molecules and ligands with dynamic RNA loops and to optimize lead compounds targeting RNA repeat expansions via inclusion of functional groups. Results will be used to facilitate drug design targeting RNA. Through a series of pilot studies, I have demonstrated how a more precise RNA force field improves the predictions. The objective of this proposal is to utilize this state-of-art RNA force field jointly with ever-increasing computational power to provide unique solutions in RNA-targeting pharmacotherapies. In Aim 1, a physics-based novel method will be created to predict the binding properties of small molecules targeting dynamic RNA loops. In Aim 2, I propose to develop a computational tool to optimize the binding properties of small molecules targeting RNA repeats via inclusion of functional groups. In Aim 3, design principles of artificial ligands targeting RNA repeats will be discovered using computational methods. This project will dramatically expand our understanding on how RNA loops fold and interact with small molecules and ligands. It will also have broader and potentially therapeutic implications for understanding RNA molecule interaction with other types of proteins such as the RNA-induced silencing complex, nucleic acid chaperones, and RNP complexes. This proposal takes advantage of a collaboration with Scripps Research Institute (Jupiter, FL). Furthermore, the research environment will provide numerous opportunities for career development of undergraduate and graduate students through national research presentations, collaborations, and training in the responsible conduct of research.

项目摘要。 RNA策划了如何控制关键生物学功能，包括催化，基因表达，酶活性和蛋白质折叠。基因表达的不调节会导致失调 RNA引起许多可遗传的疾病，例如肌营养不良，亨廷顿氏病和脆弱 X综合征由RNA转录物引起的，其中包含扩展的重复序列。该提议旨在创造独特的调查小分子和配体与动态RNA循环的相互作用的计算工具通过包含官能团来优化靶向RNA重复扩展的铅化合物。结果将用于促进针对RNA的药物设计。通过一系列试验研究，我证明了更精确的RNA力场如何改善预测。该提议的目的是与越来越多的计算能力在靶向RNA的药物治疗中提供独特的解决方案。在 AIM 1，将创建一种基于物理学的新方法来预测小分子的结合特性靶向动态RNA环。在AIM 2中，我建议开发一种计算工具来优化绑定通过包含官能团的小分子的靶向RNA重复的特性。在AIM 3中设计将使用计算方法发现靶向RNA重复序列的人工配体的原理。该项目将极大地扩展我们对RNA循环折叠和与之互动的理解小分子和配体。它也将对了解RNA分子与其他类型的蛋白质（例如RNA诱导的沉默）的相互作用复合物，核酸伴侣和RNP复合物。该建议利用合作与Scripps研究所（佛罗里达州木星）一起。此外，研究环境将提供众多通过国家研究的本科生和研究生的职业发展机会在负责任的研究中的演讲，合作和培训。