Ultra-Fast Structural ID of Drugs

The molecular structure of drugs determines how they work. LINX investigates quicker structural ID to aid innovation in the pharma industry.

Proteins are everywhere in our bodies – in building tissue,  bones, cell membranes and the enzymes which keep our biochemistry going. Many modern drugs and medicines work through interaction with proteins, and their interactions cannot be understood without knowing the protein shape, size, nooks and crevices – in short, its structure.

This is a difficult task, as proteins are enormous molecules. Luckily, they can be forced to form crystals (just like sugar, ice or gemstones) and their structures can then be deduced from the way the molecules stack, orient and align – i.e. the crystal structure. This, in turn, can be obtained from X-ray crystallography. However, for traditional methods to work crystals bigger than ca. 0.05 mm are necessary, and unfortunately protein crystals of that size can be extremely hard to prepare.

In this project LINX pursues a multitude of new techniques to reveal protein structure from extremely small crystals, which would be inadequate for traditional techniques.

The new approach  is to deduce structure from not one perfect measurement on one single crystal, but from a thousand imperfect measurements on a thousand smaller ones. In other words, getting a complete picture by jig-saw puzzle rather than a single photograph. The scope of this strategy is huge, as it can be made applicable to proteins that have so far been impossible to analyse. Making it work – and ultimately routine – would be a huge step forward for the ability to develop new drugs and treatments for a troubled world.

Techniques and Methods

The overarching goal of the project is to apply advanced uses of macromolecular X-ray  crystallography and facilities to facilitate structure determination of difficult drug targets that can guide the design and development of small-molecule and protein-based drugs. The projects will require state-of-the-art uses of new crystallization techniques (e.g. lipid-based crystallization of membrane proteins), sample presentation modes (e.g. multiple microcrystals for serial crystallography, or in situ), data collection protocols (e.g. serial crystallography), data processing techniques and capacities (e.g. serial crystallography), and structure determination methods (e.g. sulphur-SAD and antibody-based phasing).

Definition of scientific issues

  • Crystallization of prioritized targets.
  • Data acquisition using state-of-the-art facilities and methodologies.
  • Structure determination and analysis.
  • Working with beamlines on improving applications and processes

Crystallization and preliminary studies will be performed at AU and Novo Nordisk. AU will develop serial crystallography approaches and implementations based on preliminary insights and expertise from XFEL studies and ongoing research activities.

Data collection will be performed at synchrotron beamlines at PETRA3 in Hamburg, MAX IV in Lund, and Diamond Light Source in the UK, eventually also at the European XFEL in Hamburg. Input to the design and capabilities of the MicroMAX and BioMAX beamlines at MAX IV supporting high-throughput crystallography and its alignment with compound screening will be provided by AU.

Structure determination will be performed at AU and Novo Nordisk

Project Information

Participants: Novo Nordisk, Aarhus University.
High-throughput structure determination of drug targets (FP05.001, Drug discovery).