More efficient drug screening enabled by new NMR method

A popular approach in early drug discovery is “fragment-based screening”. In this strategy small molecular building blocks (fragments) are identified that can be used to build a specific drug against a given disease – much like identifying the a set of lego bricks to build a small object.

Such fragments will only bind weakly to a target protein responsible for a disease, such that a highly sensitive method is required to detect such interactions. Nuclear magnetic resonance (NMR) is such a method. However, it requires relatively large amounts of the target protein, which is usually expensive to produce.

Here, a new NMR experiment is presented, with which the amount of required protein is reduced by 8–40 fold. On standard NMR instruments a 10-fold reduction is possible, and on the most modern instruments, like the recently acquired 1.2 GHz instrument of the Swiss National NMR facility, a 40-fold reduction of protein amount is achievable.

This work was carried out in the context of the ERC Synergy funded project “HiSCORE”, which aims at redefining the role of NMR in drug discovery by developing novel technologies. In addition to scientists at ETH, groups in Paris, Karlsruhe and Nijmegen are part of this endeavour. For this project, also the instrument vendor Bruker was on board, by providing access to their most recent hardware.

In summary, the new approach was highly successful with four different drug targets, and we thus expect that this new NMR approach will become the standard way of screening for fragments and support drug discovery efforts for many diseases.

Link to the paper in external page "Angewandte Chemie International Edition".