In Silico Drug Design Targeting RNA Repeat Expansions

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。基因表达的失调导致RNA的失调， 导致许多遗传性疾病，如强直性肌营养不良症，亨廷顿氏病和脆性X综合征 是由含有扩展重复序列的RNA转录物引起的。该提案旨在创建独特的计算 研究小分子和配体与动态RNA环相互作用的工具， 通过包含官能团靶向RNA重复扩增的化合物。结果将用于 促进靶向RNA的药物设计。 通过一系列的试点研究，我已经证明了一个更精确的RNA力场如何改善 预测。这项提案的目的是利用这种最先进的RNA力场， 提高计算能力，为RNA靶向药物治疗提供独特的解决方案。在目标1中，a 建立了一种基于物理的新方法来预测靶向小分子的结合特性 动态RNA环。在目标2中，我建议开发一种计算工具来优化 通过包含官能团靶向RNA重复的小分子。在目标3中， 靶向RNA重复序列的配体将使用计算方法发现。 这个项目将极大地扩展我们对RNA环如何折叠和与小分子相互作用的理解。 分子和配体。它也将对理解RNA具有更广泛的潜在治疗意义 分子与其他类型的蛋白质相互作用，如RNA诱导的沉默复合物，核酸 分子伴侣和RNP复合物。该提案利用了与Scripps Research的合作 研究所（Jupiter，FL）。此外，研究环境将提供许多职业发展机会。 通过国家研究报告、合作，培养本科生和研究生， 以及负责任地进行研究的培训。

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.