A microED pipeline for the pharmaceutical and biotechnology industry

适用于制药和生物技术行业的 microED 管道

基本信息

批准号：
10402253
负责人：
Jessica Fox Bruhn
金额：
$ 68.37万
依托单位：
NANOIMAGING SERVICES, INC.
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-06-01 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10402253
关键词：
3-Dimensional Acetaminophen Address Algorithms Automation Biological Products Biotechnology Biotin Client Clinic Collection Commercial Sectors Complex Computer software Crystallization Data Data Collection Data Set Development Drug Costs Drug Design Electron Microscope Ensure Event Feedback Goals Handedness Health Hour Human Image Industrialization Industry Knowledge Maps Methods Micro Electron Diffraction Microscope Modeling Molecular Molecular Target Natural Products Online Systems Peptides Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacologic Substance Phase Preparation Procedures Process Progesterone Property Proteins Reproducibility Research Resolution Robot Rotation Sampling Series Services Specificity Specimen Speed Structure System Techniques Testing Time Work X-Ray Crystallography base chemotherapy chiral molecule computerized data processing cost crystallinity data acquisition data analysis pipeline data quality data reduction drug development drug discovery electron diffraction flexibility improved improved outcome interest microscopic imaging nanoimaging novel novel strategies programs screening small molecule statistics targeted treatment three dimensional structure transmission process

项目摘要

Project Summary/Abstract Microcrystal electron diffraction (microED) is an emerging structure determination technique of high interest to the pharmaceutical and biotechnology industries. MicroED can rapidly determine atomic-resolution structures from microcrystals with minimal sample requirements. The goal of this Phase II proposal is to develop and deliver robust service offerings for microED structure determination to the commercial sector. Improvements to critical steps in this workflow will enable analysis for any suitable sample type while offering a level of efficiency that meets the requirements of Structure-Based Drug Design (SBDD) and medicinal chemistry programs. The permissive sample requirements, minimal time requirements, and high-quality structures generated make microED an attractive structure determination technique with broad applications for small molecules, peptides, natural products, proteins and protein-drug complexes. An efficient microED pipeline will help to reduce the cost of drug development and reduce the time it takes a drug to make it into the clinic. MicroED uses a transmission electron microscope (TEM) to collect diffraction data from small crystalline samples. The steps required include transferring crystalline samples to TEM grids; collecting a series of continuous-rotation, electron-diffraction datasets from single crystals; processing the diffraction data and refining the atomic model. An initial development phase demonstrated collection of excellent quality diffraction datasets for more than 20 samples, and the ability to deliver atomic resolution maps suitable for addressing the needs of our pharmaceutical clients who took part in alpha and beta testing. New methods will be developed, and existing approaches optimized to improve every step of this pipeline, substantially increase throughput, and improve final maps and models. Specific aims include: (1) Optimizing TEM grid preparation to ensure the transfer of a sufficient number of high-quality target microcrystals onto the grid substrate without damaging them or altering their properties. (2) Developing an automated, high-throughput data collection system capable of unattended, overnight data acquisition for multiple different samples, and of providing information to inform data scaling and determining handedness of chiral small molecules. (3) Automating and improving data processing, phasing and model refinement including real-time data reduction, brute force on-the-fly phasing, and investigating a wide range of new programs and methods. In parallel with the Phase II research plan, a full commercial service offering spanning the complete range of microED capabilities will be developed.

项目概要/摘要微晶电子衍射 (microED) 是一种新兴的结构测定技术，引起了人们的极大兴趣制药和生物技术行业。 MicroED 可以快速确定原子分辨率的结构从微晶中提取，样品要求极低。第二阶段提案的目标是开发和交付为商业领域的 microED 结构测定提供强大的服务。关键改进此工作流程中的步骤将能够对任何合适的样品类型进行分析，同时提供一定程度的效率满足基于结构的药物设计（SBDD）和药物化学项目的要求。这宽松的样品要求、最短的时间要求以及生成的高质量结构使得 microED 是一种有吸引力的结构测定技术，在小分子、肽、天然产物、蛋白质和蛋白质药物复合物。高效的 microED 管道将有助于降低成本药物开发并减少药物进入临床所需的时间。 MicroED 使用透射电子显微镜 (TEM) 收集小晶体的衍射数据样品。所需步骤包括将晶体样品转移至 TEM 网格；收集一系列的来自单晶的连续旋转、电子衍射数据集；处理衍射数据并精炼原子模型。初始开发阶段展示了高质量衍射数据集的收集适用于 20 多个样品，并且能够提供适合满足以下需求的原子分辨率图我们参与 alpha 和 beta 测试的制药客户。将开发新方法，并利用现有方法优化方法以改进该管道的每一步，大幅提高吞吐量并改善最终结果地图和模型。具体目标包括： (1) 优化 TEM 网格制备以确保足够的转移将大量高质量目标微晶沉积到网格基板上，而不会损坏它们或改变它们特性。 (2) 开发自动化、高通量的数据采集系统，能够实现无人值守、过夜获取多个不同样本的数据，并提供信息以告知数据缩放和确定手性小分子的旋手性。 (3) 自动化和改进数据处理、分阶段和模型细化，包括实时数据缩减、强力动态定相以及广泛的调查一系列新的计划和方法。与第二阶段研究计划并行，涵盖整个范围的全面商业服务将开发 microED 功能。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Absolute configuration determination of pharmaceutical crystalline powders by MicroED via chiral salt formation.

通过 MicroED 通过手性盐形成确定药物结晶粉末的绝对构型。

DOI：
发表时间：
2022-04-12
期刊：
影响因子：
0
作者：
Wang, Bo;Bruhn, Jessica F;Weldeab, Asmerom;Wilson, Timothy S;McGilvray, Philip T;Mashore, Michael;Song, Qiong;Scapin, Giovanna;Lin, Yiqing
通讯作者：
Lin, Yiqing

Absolute Configuration Determination of Chiral API Molecules by MicroED Analysis of Cocrystal Powders Formed Based on Cocrystal Propensity Prediction Calculations.

通过基于共晶倾向预测计算形成的共晶粉末的 MicroED 分析来确定手性 API 分子的绝对构型。

DOI：
发表时间：
2023-03-07
期刊：
影响因子：
0
作者：
Shah, Harsh S;Yuan, Jiuchuang;Xie, Tian;Yang, Zhuocen;Chang, Chao;Greenwell, Chandler;Zeng, Qun;Sun, GuangXu;Read, Brandon N;Wilson, Timothy S;Valle, Henry U;Kuang, Shanming;Wang, Jian;Sekharan, Sivakumar;Bruhn, Jessica F
通讯作者：
Bruhn, Jessica F

Small Molecule Microcrystal Electron Diffraction for the Pharmaceutical Industry-Lessons Learned From Examining Over Fifty Samples.

用于制药行业的小分子微晶电子衍射 - 从检查五十多个样品中吸取的经验教训。

DOI：
发表时间：
2021
期刊：
影响因子：
0
作者：
Bruhn, Jessica F;Scapin, Giovanna;Cheng, Anchi;Mercado, Brandon Q;Waterman, David G;Ganesh, Thejusvi;Dallakyan, Sargis;Read, Brandon N;Nieusma, Travis;Lucier, Kyle W;Mayer, Megan L;Chiang, Nicole J;Poweleit, Nicole;McGilvray, Philip T;Wilson
通讯作者：
Wilson

From Powders to Single Crystals: A Crystallographer's Toolbox for Small-Molecule Structure Determination.

从粉末到单晶：用于小分子结构测定的晶体学家工具箱。