Project Description

The Road to New Drug Targets

Understanding the 3D structure of the drug target advances the design of new and more targeted drugs. The path to structural insight can be treacherous and hold many pitfalls. With this project we shall explore new technologies for structure determination of challenging drug targets – targets that so far have been out of reach.

Techniques and Methods

Discovery of new drugs is crucial to our well-being and society. At Aarhus University, the “life” division helps develop a state-of-the-art toolbox through X-ray diffraction.

Aarhus University works for LINX on two fronts, (1) hard materials – including nanomaterials – and (2) bio-materials (“life”). The latter category includes all materials of which we are made, as living beings. AU “Life” specializes in proteins, which is one of the most essential building blocks of life in everything from bacteria and up.

We humans have another interest, because many of the drugs we have and invent work through interaction with proteins in our body. For instance, one class of proteins is enzymes, the essential “assistants” to thousands of chemical reactions which keep our bodies going minute by minute. Development of new enzymes, or ways to modify their activity, is a crucial topic to pharma industry.

Proteins themselves are enormous molecules which can bend, twist and fold in numerous ways. Their specific shape and all their nooks and crevices are key to “what” they do and “how” they work. This is referred to as their structure. Knowing about this is an essential avenue to understanding the actions of drugs – and of how they can possibly be improved.

Interestingly, in their pure form proteins can form crystals just like sugar, ice or gemstones. This ability enables structural studies by crystallography – i.e. deriving information about individual protein molecules through the “window” of how they stack, order and align in the crystal. This is the expertise of the AU “Life” division in LINX.

The division constantly tries to push the limits of modern protein crystallography. Three particular fronts are pursued:

  • Serial crystallography
  • In situ crystallography
  • Fragment screening

Serial Crystallography

Serial crystallography focuses on using powerful X-ray sources (e.g. synchrotrons) to greatly enhance the whole process of identifying protein structures. One frequent problem is that protein crystals are difficult to make – the big molecules do not want to stack properly. Without “nice” crystals, the crystallographic technique breaks down, and traditionally a certain crystal size has – in practice – been necessary. However, AU pursues a new alternative, to piece together one complete dataset from thousands of incomplete ones – each collected from a separate, tiny crystal which would in itself have been inadequate for a “classic” measurement. Thus, if “structure” was a photograph, the old standard technique would attempt to capture the entire picture in a single shot, whereas the new one instead spits out a few thousand jig-saw puzzle pieces – ready to be computer-assembled by state-of-the-art software.

In Situ Crystallography

In situ crystallography deals with the problem that “good” protein crystals are often hard to spot. A single attempt at making them often produces numerous crystals of varying sizes and shapes. Traditionally, “good” crystals have more or less been chosen for how pretty they look, assuming that a “nice outside implies a nice inside”. This is, however, far from always true. In situ crystallography is the art of screening thousands of individual protein crystals quickly and efficiently, with the purpose of instantly assessing their quality – and spotting those which can produce the best data sets. No more guesswork.

Fragment Screening

Fragment screening is new, promising path towards developing medication. Drug molecules are typically quite big and they interact in very particular ways with specific spots on the (even larger) proteins. What has annoyed researchers is that many good spots may be hidden in the folds and crevices of the protein molecules, inaccessible to the drugs, simply because of their bulky size. The power of the  “fragment” approach is that it works on a much smaller size scale, focusing instead on the individual, chemical building blocks of drugs – those crucial bits which are actually and ultimately responsible for the interaction between drug and protein. In the analogy of Lego blocks, the traditional method worked with pre-assembled clusters of glued-together blocks, which would not necessarily connect anywhere they could. However, the “fragment” method is based on individual blocks, i.e. a much more detailed level. The outcome is a much better assessment of how, why and where drugs and proteins interact, enabling a new route to improved medication.

Through its energetic push within all these fields, AU “Life” aims at moving the state-of-the-art university research closer to relevant LINX member companies. The grand goal is to make the techniques “plug and play”.

Project Information

Participants: Aarhus University.
Title: Developing techniques for next generation macromolecular X-ray crystallography (AU GDP).