Böttcher Jark, Jestel Anja, Kiefersauer Reiner, Krapp Stephan, Nagel Susanna, Steinbacher Stefan, Steuber Holger
Proteros biostructures GmbH, Am Klopferspitz 19, Martinsried, Germany.
Methods Enzymol. 2011;493:61-89. doi: 10.1016/B978-0-12-381274-2.00003-0.
In the past two decades, fragment-based approaches have evolved as a predominant strategy in lead discovery. The availability of structural information on the interaction geometries of binding fragments is key to successful structure-guided fragment-to-lead evolution. In this chapter, we illustrate methodological advances for protein-fragment crystal structure generation in order to offer general lessons on the importance of fragment properties and the most appropriate crystallographic setup to evaluate them. We analyze elaborate protocols, methods, and clues applied to challenging complex formation projects. The results should assist medicinal chemists to select the most promising targets and strategies for fragment-based crystallography as well as provide a tutorial to structural biologists who attempt to determine protein-fragment structures.
在过去二十年中，基于片段的方法已发展成为先导化合物发现的主要策略。关于结合片段相互作用几何结构的结构信息的可用性是成功进行结构导向的片段到先导化合物演化的关键。在本章中，我们阐述了蛋白质-片段晶体结构生成的方法进展，以便就片段性质的重要性以及评估这些性质的最合适晶体学设置提供一般性经验教训。我们分析了应用于具有挑战性的复合物形成项目的详细方案、方法和线索。这些结果应有助于药物化学家选择基于片段的晶体学中最有前景的靶点和策略，并为试图确定蛋白质-片段结构的结构生物学家提供一份指南。
