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。基因表达失调会导致基因表达失调 RNA，导致许多遗传性疾病，如强直性肌营养不良、亨廷顿舞蹈病和脆性肌病 由含有扩展重复序列的 RNA 转录物引起的 X 综合征。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 通过包含官能团来优化针对 RNA 重复扩增的先导化合物。 结果将用于促进针对 RNA 的药物设计。 通过一系列试点研究，我展示了更精确的 RNA 力场如何改善 的预测。该提案的目标是联合利用这种最先进的 RNA 力场 不断增强的计算能力为 RNA 靶向药物疗法提供独特的解决方案。在 目标 1，将创建一种基于物理的新方法来预测小分子的结合特性 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绑定 通过包含功能基团靶向 RNA 重复的小分子的特性。在目标 3 中，设计 靶向RNA重复的人工配体的原理将通过计算方法被发现。 该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影响： 了解 RNA 分子与其他类型蛋白质的相互作用，例如 RNA 诱导的沉默 复合物、核酸伴侣和 RNP 复合物。该提案利用了合作的优势 与斯克里普斯研究所（佛罗里达州朱庇特）合作。此外，研究环境将提供大量 通过国家研究为本科生和研究生提供职业发展的机会 负责任的研究行为的演示、合作和培训。