Core D: Structural and Computational Virology

核心 D：结构和计算病毒学

基本信息

批准号：
10522808
负责人：
Rommie E Amaro
金额：
$ 727.13万
依托单位：
UNIVERSITY OF MINNESOTA
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：
2022-05-16 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10522808
关键词：
Active Sites Allosteric Regulation Antibodies Antiviral Agents Area Binding Biological Biological Process Biophysics Chemicals Complement Complex Computer Models Computing Methodologies Cryoelectron Microscopy Data Data Set Development Drug Design Drug Targeting Foundations Ligand Binding Link Location Membrane Glycoproteins Methods Microscopy Midwestern United States Modeling Modification Molecular Mutation NMR Spectroscopy Nuclear Magnetic Resonance Nucleic Acids Peptide Hydrolases Pharmaceutical Chemistry Pharmaceutical Preparations Physiological Polysaccharides Post-Translational Protein Processing Process Proteins Resolution Roentgen Rays Shapes Solvents Structural Biologist Structure Techniques Translating Viral Viral Proteins Virus Vision Work X-Ray Crystallography antiviral drug development biophysical properties biophysical techniques design drug development drug discovery drug structure experience experimental study flexibility helicase in vivo inhibitor innovation insight interest lead optimization models and simulation molecular assembly/self assembly molecular dynamics nanobodies novel nuclease rational design simulation small molecule small molecule inhibitor structural biology targeted treatment trend virology virtual screening

项目摘要

Core D – Structural and Computational Virology ABSTRACT Core D aims to characterize the structure and dynamics of viral protein targets in complex with small molecule and nanobody inhibitors, in support of all Projects within the Midwest AViDD Center. Structural characterization of viral targets in complex with inhibitors provides a valuable framework for the rational design and modification of small molecules as they advance from the initial hit stage, through lead optimization, and beyond. Structure and dynamics of these co-complexes also informs on mechanism of action. In Core D, we assemble a collaborative team of world experts to provide comprehensive descriptions of structures and dynamics of targets of interest. We will employ x-ray crystallography, cryoelectron microscopy, and NMR spectroscopy to provide experimental characterization. Subsequently, computational biophysical techniques, including all-atom molecular dynamics simulations, computational solvent mapping, and other methods will be used to create accurate models of the targets in vivo (e.g., with any mutations from experiment reverted to wild type, addition of N- and O-linked glycans and other post-translational modifications) and explore target dynamics under relevant physiological conditions. Altogether, our collective efforts will provide informative insights into the structure and dynamics of Midwest AViDD Center targets, and accelerate the discovery and design of new and safer medications.

核心D - 结构和计算病毒学抽象的核心D旨在表征与小分子复合物中病毒蛋白靶标的结构和动力学和纳米抑制剂，以支持中西部Avidd中心内的所有项目。结构表征与抑制剂复杂的病毒靶标的，为理性设计和修改提供了一个宝贵的框架小分子从初始命中阶段，铅优化及以后发展时。结构这些共复合物的动力学也告知了作用机理。在核心D中，我们组装一个世界专家的协作团队，提供有关结构和动态的全面描述感兴趣的目标。我们将采用X射线晶体学，冷冻电子显微镜和NMR光谱提供实验表征。随后，计算生物物理技术，包括全部原子分子动力学模拟，计算溶剂映射和其他方法将用于创建体内目标的准确模型（例如，从实验中的任何突变逆转为野生型，加法 N-和O连接的聚糖以及其他翻译后修饰）并探索目标动态相关的身体状况。总的来说，我们的集体努力将为您提供信息的见解中西部Avidd中心目标的结构和动力学，并加速了新和设计的发现和设计安全的药物。