TRD3: Peptide inhibitors and small molecule drug discovery

TRD3.多肽抑制剂与小分子药物发现--Gonen(铅) 摘要 小分子药物和多肽抑制剂的发现、设计和合成是缓慢和低效的，因为它 成功的结构表征需要大量的材料。在过去的50年里，核磁共振和 为了应对这一挑战，还开发了其他强大的光谱技术。虽然几乎所有的人都依赖于 关于原子连接性的推断，需要使用对小分子结构的明确确定 X射线和/或中子衍射法。在现实中，X射线结晶学很少应用于这样的情况 常规药物开发。这是因为执行结晶分析需要大量的工作。 由于需要大量的材料，而标本通常只在 毫微克数。我们最近证明了微晶电子衍射(MicroED)可用于 一种强大的、潜在的常规方法，用于明确确定小分子的结构。vbl.使用 看似无定形的粉末和多肽直接从纯化柱上出来，而不需要进一步结晶， MicroED仅使用毫微克量的材料即可提供原子分辨率结构。这一过程花了 只需几分钟，只需要很少的人力。在这里，我们将建立MicroED作为结构的一种选择方法 通过高通量测定小分子并作为药物开发的分析工具 用于小分子结构测定的管道。我们将把MicroED的使用扩展到结构 用于药物发现和研究神经毒素和神经毒剂的天然产物的测定 阻断离子通道。目标是：1.实时结构测定和高通量药物发现； 评价MicroED方法研究天然产物的适用性；3.神经毒素、神经毒剂、 以及中和剂的鉴定。总体而言，我们将制定小批量样品制备程序。 分子、天然产物和毒素，并通过 协助药物发现过程的长期目标。

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.