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Updated: May 5, 2026

Workflow and Tools for Crystallographic Fragment Screening at the Helmholtz-Zentrum Berlin

Workflow and Tools for Crystallographic Fragment Screening at the Helmholtz-Zentrum Berlin

Published on: March 3, 2021

欧盟-OPENSCREEN碎片库的设计,质量和验证,准备成为一个高吞吐量选集合

Xavier Jalencas¹, Hannes Berg^2,3, Ludvik Olai Espeland^4,5

¹Research Group on Systems Pharmacology, Research Program on Biomedical Informatics (GRIB), IMIM Hospital del Mar Medical Research Institute Parc de Recerca Biomèdica (PRBB), Doctor Aiguader 88 08003 Barcelona Spain jmestres@imim.es.

RSC medicinal chemistry

|April 26, 2024

概括

欧洲碎片选图书馆 (EFSL) 通过提供1056个微型和小型化学碎片来帮助早期药物发现. 这家图书馆有助于识别碎片命中,包括针对细菌FabF.的新型抗生素化合物.

科学领域:

化学生物学化学生物学
药物发现药物发现药物发现
结构生物学结构生物学

背景情况:

欧盟-OPENSCREEN (EU-OS) 欧洲研究基础设施联盟 (ERIC) 支持化学生物学和早期药物发现.
欧盟-OS维护欧洲化学生物学图书馆 (ECBL) ~100,000小分子和学术化合物.

研究的目的:

描述欧洲碎片选图书馆 (EFSL) 的计算设计,质量控制和选.
证明EFSL在识别药物发现的碎片命中中中的实用性,以抗生素标为例.

主要方法:

为了创建EFSL (1056个片段),ECBL的计算设计和亚结构分析.
使用多种结构和生物物理方法进行碎片选活动.
生物层干扰测量 (BLI) 选EFSL对β-基酸-ACP合成酶2 (FabF) 的检测.
射线晶体学用于断片碰撞和后续化合物的结合确认.

主要成果:

在使用EFSL的八个活动中成功识别了碎片命中.
一个35μM片段的识别,该片段准了细菌FabF.
通过X射线结晶学 (PDB 8PJ0) 确认碎片结合.
鉴定和结构确认 (PDB 8R0I,8R1V) 的两个后续化合物与改善的结合.

结论:

在早期药物发现方面,EFSL是学术和工业研究人员的宝贵资源.
在EFSL成功地确定了新的碎片线索,包括潜在的抗生素化合物.
综合碎片查和药物化学努力加快了药物发现过程.

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