TRD3: Peptide inhibitors and small molecule drug discovery

TRD3：肽抑制剂和小分子药物发现

• 批准号: 10641822
• 负责人: Tamir Gonen
• 金额: $ 20.76万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10641822
• 关键词: Address; Amino Acids; Bacterial Genome; Binding; Biological Assay; Cessation of life; Collection; Communities; Crystallization; Databases; Development; Drug Industry; Electron Diffraction Microscopy; Evaluation; Fungal Genome; Goals; Growth; Human Resources; Ion Channel; Laboratories; Lead; Libraries; Life; Maps; Medicine; Methodology; Methods; Natural Product Drug; Natural Products; Neurotoxins; Neutron Diffraction; Paralysed; Peptides; Pharmaceutical Preparations; Powder dose form; Preparation; Procedures; Process; Proteins; Resolution; Ribosomes; Roentgen Rays; Sampling; Specimen; Structure; Techniques; Technology; Time; Toxin; X-Ray Crystallography; analytical method; analytical tool; design; drug development; drug discovery; electron diffraction; imaging facilities; inhibitor; nanocrystal; nerve agent; polypeptide; receptor; small molecule

TRD3. Peptide inhibitors and small molecule drug discovery - Gonen (Lead) Summary The discovery, design, and synthesis of small molecule drugs and peptide inhibitors is slow and inefficient as it requires large amounts of material for successful structural characterization. Over the past 50 years, NMR and other powerful spectroscopic techniques were developed to address this challenge. While almost all of them rely on inference of atomic connectivity, the unambiguous determination of a small molecule's structure requires use of X-ray and/or neutron diffraction methods. In reality, X-ray crystallography is rarely applied in such cases for routine drug development. This is because of the significant effort is required for performing crystallization assays and because of the large quantity of material that is needed, while specimens are often available only in femtogram amounts. We recently demonstrated that microcrystal electron diffraction (MicroED) can be used as a powerful and potentially routine method for unambiguous structural determination of small molecules. Using seemingly amorphous powders and peptides straight off of a purification column without further crystallization, MicroED delivered atomic resolution structures using only femtogram amounts of material. The process took minutes and required little personnel effort. Here, we will establish MicroED as a method of choice for structure determination of small molecules and as an analytical tool for drug development through high-throughput pipelines for small molecule structure determination. We will extend the use of MicroED to structure determination of natural products for drug discovery efforts and study neurotoxins and nerve agents that typically block ion channels. The aims are: 1. Real-time structure determination and high-throughput drug discovery; 2. Evaluation of MicroED methodologies' applicability to studying natural products; 3. Neurotoxins, nerve agents, and identification of neutralizing agents. Overall, we will develop procedures for sample preparation for small molecules, natural products and toxins, and deliver a large library of their atomic resolution structures with the long-term goal of aiding drug discovery process.

TRD 3.肽抑制剂和小分子药物发现- Gonen（负责人） 总结 小分子药物和肽抑制剂的发现、设计和合成是缓慢和低效的，因为其 需要大量的材料用于成功的结构表征。在过去的50年里，NMR和 开发了其他强大的光谱技术来解决这一挑战。而几乎所有的人都依赖于 关于原子连接性的推断，要明确地确定小分子的结构，就需要使用 X射线和/或中子衍射方法。实际上，X射线晶体学很少应用于这种情况， 常规药物开发。这是因为进行结晶分析需要大量的工作 由于需要大量的材料，而标本往往只能在 毫微微克量。我们最近证明，微晶电子衍射（MicroED）可以用作 一个强大的和潜在的常规方法，明确的结构测定的小分子。使用 表面上无定形的粉末和肽直接离开纯化柱而没有进一步结晶， MicroED仅使用毫微微克量的材料即可提供原子分辨率的结构。这个过程花了 几分钟，需要很少的人力。在这里，我们将建立MicroED作为结构的选择方法， 作为高通量药物开发的分析工具 用于小分子结构测定的管道。我们将扩大使用MicroED结构 确定药物发现工作的天然产物，并研究神经毒素和神经毒剂， 阻断离子通道。目标是：1.实时结构测定和高通量药物发现; 2. 评价MicroED方法学对天然产物研究的适用性; 3.神经毒素，神经毒剂， 和中和剂的鉴定。总的来说，我们将制定样品制备程序， 分子，天然产物和毒素，并提供其原子分辨率结构的大型库， 协助药物发现过程的长期目标。