Structural Biology Core

结构生物学核心

• 批准号: 10513867
• 负责人: John Damon Chodera
• 金额: $ 128.87万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 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/10513867
• 关键词: 2019-nCoV; Acceleration; Binding Proteins; Binding Sites; Collaborations; Crystallization; Crystallography; Data; Development; Diamond; Disease; Ensure; Goals; Lead; Ligands; Light; Logistics; Methods; Oral; Pharmaceutical Chemistry; Protease Inhibitor; Proteins; Public Domains; Source; Structure; Synchrotrons; Techniques; Technology; Time; Viral; biophysical techniques; coronavirus disease; lead optimization; novel; novel therapeutics; open data; process optimization; screening; small molecule; structural biology

Effective structural enablement with short turn-around and rapid dissemination of well annotated structural data provides significant impact to the hit-to-lead and lead optimization processes. This has been exemplified by the contribution of Diamond Light Source to the COVID Moonshot - an open science collaboration that developed a novel non-peptidomimetic small molecule orally bioavailable SARS-CoV-2 main viral protease (Mpro) inhibitor with potent antiviral activity starting from a high-throughput fragment screen in less than 12 months. This project has demonstrated that achieving real-time turnaround of structural data is not only technically feasible, but scientifically crucial to accelerating compound progression. Additionally, crystallographic fragment screening is a well-validated method for mapping protein ligand binding sites and identifying starting points for the development of novel therapeutics for a wide range of diseases. This technique is highly sensitive and owing to developments in synchrotron technology plus the establishment of dedicated screening facilities, such as the world-first XChem platform at Diamond Light Source, the throughput is now comparable to other biophysical techniques such as NMR and SPR with the advantage that structural information is immediately available to drive fragment-tolead development. The Structural Biology Core has been specifically situated at the Diamond Light Source's XChem facility to capitalize on its world-leading high-throughput crystallography capabilities in order to implement the logistics and technologies required to consistently achieve the acceleration required to meet the ASAP AViDD Center's ambitious medicinal chemistry goals. This core will be responsible for the successful delivery of crystallographic fragment screens, the rapid turn-around of protein-ligand crystal structures for all compounds generated by this center and ensuring all crystal structures are promptly available, at high quality and fully annotated, in the public domain.

有效的结构性启用，并具有较短的转弯和 快速传播良好注释的结构数据对命中至铅的影响很大， 铅优化过程。钻石光源对 Covid Moonshot-开放的科学合作，开发了一种新颖的非肽型小型小型 分子口服生物利用的SARS-COV-2主病毒蛋白酶（MPRO）抑制剂具有有效的抗病毒 活动从不到12个月的高通量片段开始。这个项目有 证明实现结构数据的实时周转不仅在技术上是可行的，而且是 科学对于加速复合进展至关重要。 此外，晶体学片段筛选是绘制蛋白质配体的验证良好的方法 绑定位点并识别开发新疗法的起点 疾病。该技术高度敏感，并且由于同步器技术的发展 加上建立专门的筛选设施，例如世界优先的Xchem平台 钻石光源，吞吐量现在与其他生物物理技术（例如NMR）相媲美 SPR具有优势，即立即使用结构信息来驱动片段 - 托管 发展。 结构生物学核心专门位于钻石光源的Xchem 利用其世界领先的高通量晶体学能力的设施 实施一致达到所需的加速所需的物流和技术 实现ASAP AVIDD中心的雄心勃勃的药物化学目标。 该核心将负责成功交付晶体学碎片屏幕，快速 该中心产生的所有化合物的蛋白质晶体结构的转弯和确保 在公共领域，所有晶体结构都迅速以高质量和完全注释的方式提供。