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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：
10796593
负责人：
Ilyas Yildirim
金额：
$ 9.04万
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

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协调关键生物功能的控制方式，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RNA失调，导致许多遗传性疾病，如强直性肌营养不良、亨廷顿病和脆性 X 综合征由含有扩展重复序列的 RNA 转录物引起。该提案旨在创建独特的计算研究小分子和配体与动态 RNA 环的相互作用并优化先导化合物的工具通过包含官能团来靶向 RNA 重复扩增的化合物。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 力场如何改善预测。该提案的目标是利用这种最先进的 RNA 力场与永远- 提高计算能力，为 RNA 靶向药物疗法提供独特的解决方案。在目标 1 中，将创建基于物理学的新方法来预测小分子靶向的结合特性动态RNA环。在目标 2 中，我建议开发一种计算工具来优化通过包含功能基团靶向 RNA 重复序列的小分子。在目标3中，人工的设计原则靶向RNA重复的配体将通过计算方法被发现。该项目将极大地扩展我们对 RNA 环如何折叠以及如何与小分子相互作用的理解。分子和配体。它还将对理解 RNA 产生更广泛和潜在的治疗意义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、核酸分子伴侣和 RNP 复合物。该提案利用了与斯克里普斯研究中心的合作研究所（佛罗里达州朱庇特）。此外，研究环境将提供大量的职业机会通过国家研究报告、合作来培养本科生和研究生，以及负责任地进行研究的培训。