In Silico Drug Design Targeting RNA Repeat Expansions

针对 RNA 重复扩增的计算机药物设计

• 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
• 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

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协调如何控制关键的生物功能，包括催化，基因 表达、酶活性和蛋白质折叠。基因表达的失调会导致 RNA，它导致许多遗传性疾病，如肌强直性营养不良症，亨廷顿病，和脆性 X综合征是由含有扩展重复序列的RNA转录物引起的。该提案旨在创造独特的 研究小分子和配体与动态RNA环的相互作用的计算工具， 通过引入官能团优化靶向RNA重复扩增的先导化合物。 结果将用于促进靶向RNA的药物设计。 通过一系列的初步研究，我已经证明了一个更精确的RNA力场是如何提高 预测。这项提议的目的是利用这种最先进的RNA力场， 不断增加的计算能力，为RNA靶向药物治疗提供独特的解决方案。在 目的1，建立一种基于物理的预测小分子结合性质的新方法 靶向动态RNA环。在目标2中，我建议开发一种计算工具来优化结合 通过包含官能团靶向RNA重复序列的小分子的性质。在目标3中， 将使用计算方法发现靶向RNA重复序列的人工配体的原理。 这个项目将极大地扩展我们对RNA环如何折叠和相互作用的理解。 小分子和配体。它还将对以下疾病产生更广泛和潜在的治疗意义： 理解RNA分子与其他类型蛋白质的相互作用，如RNA诱导的沉默 复合物、核酸分子伴侣和RNP复合物。该提案利用了一项合作 Scripps Research Institute（Jupiter，FL）。此外，研究环境将提供许多 通过国家研究为本科生和研究生提供职业发展机会 介绍，合作，并在负责任的研究行为的培训。