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。基因表达的错误调节导致RNA的失调，这是 导致许多遗传性疾病，如强直性肌营养不良症、亨廷顿病和脆性X综合征 由含有扩展重复序列的RNA转录本引起。该提案寻求创建独特的计算 研究小分子和配体与动态RNA环相互作用和优化铅的工具 通过包含官能团来靶向RNA重复序列扩张的化合物。结果将用于 促进针对RNA的药物设计。 通过一系列的初步研究，我已经演示了更精确的RNA力场如何改善 预测。这项提议的目标是利用这一最先进的RNA力场与有史以来- 提高计算能力，在RNA靶向药物疗法中提供独特的解决方案。在目标1中，一个 基于物理的新方法将被用来预测靶向小分子的结合性质 动态RNA循环。在目标2中，我建议开发一个计算工具来优化结合属性 靶向RNA的小分子通过包含官能团来重复。第三章，人工神经网络的设计原则 针对RNA重复序列的配体将使用计算方法来发现。 这个项目将极大地扩展我们对RNA环如何折叠以及如何与Small相互作用的理解 分子和配体。它还将对理解RNA具有更广泛和潜在的治疗意义 与其他类型蛋白质的分子相互作用，如RNA诱导的沉默复合体、核酸 伴侣和RNP复合体。这项提议利用了与斯克里普斯研究公司的合作 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、 以及负责任的研究行为方面的培训。

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.