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基因表达的失调 导致许多遗传性疾病的RNA，如强直性肌营养不良症、亨廷顿氏病和脆性 由含有扩展重复序列的RNA转录本引起的X综合征。该提案旨在创建独特的 研究小分子和配体与动态RNA环和 通过包含官能团来优化靶向RNA重复扩增的先导化合物。 结果将被用于促进针对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力场是如何改进的。 这些预测。这项提议的目标是利用这一最先进的RNA力场与 不断增加的计算能力，在RNA靶向药物疗法中提供独特的解决方案。在……里面 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性质 瞄准动态的RNA环。在目标2中，我建议开发一个计算工具来优化绑定 通过包含官能团来靶向RNA重复序列的小分子的性质。在目标3中，设计 针对RNA重复序列的人工配体的原理将通过计算方法来发现。 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的潜在治疗影响 了解RNA分子与其他类型蛋白质的相互作用，如RNA诱导的沉默 复合体、核酸伴侣和RNP复合体。该提案利用了协作 与斯克里普斯研究所(佛罗里达州朱庇特)合作。此外，研究环境将提供许多 通过国家研究为本科生和研究生提供职业发展机会 在负责任的研究行为方面的陈述、合作和培训。

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.