Department of Chemistry and Molecular Biology, University of Gothenburg, Box 462, SE-405 30 Gothenburg, Sweden.
Discovery Biology, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Pepparedsleden 1, SE-431 83 Gothenburg, Sweden.
IUCrJ. 2024 Sep 1;11(Pt 5):831-842. doi: 10.1107/S2052252524006134.
Structure-based drug design is highly dependent on the availability of structures of the protein of interest in complex with lead compounds. Ideally, this information can be used to guide the chemical optimization of a compound into a pharmaceutical drug candidate. A limitation of the main structural method used today - conventional X-ray crystallography - is that it only provides structural information about the protein complex in its frozen state. Serial crystallography is a relatively new approach that offers the possibility to study protein structures at room temperature (RT). Here, we explore the use of serial crystallography to determine the structures of the pharmaceutical target, soluble epoxide hydrolase. We introduce a new method to screen for optimal microcrystallization conditions suitable for use in serial crystallography and present a number of RT ligand-bound structures of our target protein. From a comparison between the RT structural data and previously published cryo-temperature structures, we describe an example of a temperature-dependent difference in the ligand-binding mode and observe that flexible loops are better resolved at RT. Finally, we discuss the current limitations and potential future advances of serial crystallography for use within pharmaceutical drug discovery.
基于结构的药物设计高度依赖于目标蛋白与先导化合物复合物的结构的可用性。理想情况下，这些信息可以用于指导化合物的化学优化，将其转化为候选药物。目前主要结构方法（传统 X 射线晶体学）的一个限制是，它只能提供蛋白质复合物在冻结状态下的结构信息。连续结晶学是一种相对较新的方法，它提供了在室温下研究蛋白质结构的可能性。在这里，我们探索了使用连续结晶学来确定药物靶标可溶性环氧化物水解酶的结构。我们引入了一种新的方法来筛选适合连续结晶学使用的最佳微结晶条件，并呈现了我们目标蛋白的一些 RT 配体结合结构。通过比较 RT 结构数据和以前发表的低温结构数据，我们描述了一个配体结合模式随温度变化的例子，并观察到在 RT 下柔性环更好地解析。最后，我们讨论了连续结晶学在药物发现中的当前限制和潜在的未来进展。
