Abstract
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, rotational cryo-crystallography, is that it only provides structural information of 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. Here, we explore the use of serial crystallography to determine 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 room-temperature ligand-bound structures of our target protein. From a comparison between the room-temperature structural data and previously published cryo-temperature structures, we describe an example of a temperature-dependent difference in ligand-binding mode and observe that flexible loops are better resolved at ambient temperature. Finally, we discuss current limitations and potential future advances of serial crystallography for use within pharmaceutical drug discovery.
Competing Interest Statement
GB is a co-founder of the company Serial X. HK is an AstraZeneca full-time employee and may own stock or stock options.