Compound screening breakthrough promises more efficient drug discovery

Graphical representation of ‘Rule of 3’ fragment properties proposed by Robin Carr and Miles Congreve in their landmark 2003 paper, published in the Journal Drug Discovery Today, 8:876–7. Figure an extract from the whitepaper 20 years of fragment-based discovery leads to success with “undruggable” targets, authored for LGC by Joe Lackey PhD in 2023.  

UK scientists have developed a revolutionary screening procedure that greatly improves the efficiency of fragment-based drug discovery (FBDD).

For the first time, the R2KD Test ranks compounds according to the strength of their interaction with clinical targets – enabling quicker identification of the molecules that offer most promise as potential drugs.

This in turn could transform FBDD by helping research teams focus their time and resources on only the most suitable compounds.

“We are thrilled to have developed a new tool that will make it easier and quicker to find the drugs of the future,” said lead author Dr Maggie Liu, from London’s Institute of Cancer Research (ICR).

The fruit of a five year study, R2KD uses the drug discovery approach ligand-observed nuclear magnetic resonance (LONMR) to measure the speed at which drug fragments spin in a solution.

Since larger molecules oscillate more slowly than smaller ones, an increase in the fragment’s transverse relaxation rate – or R2 – indicates that it has reacted with a target protein.

The ICR team developed a mathematical formula to assign a binding affinity value called Kd to each fragment, then ranked them to reveal which had the strongest interactions – making the combined R2KD test the first to enable the quantitative screening of drug fragments.

“We know that our tool works in a wide Kd range of binding events, extending from 10 µM to 1 mM,” said Dr Liu.

“This is the most promising range and, therefore, the most practical choice.

“Very strong interactions that would fall outside of this range are unlikely when using fragments, and weaker interactions would make it difficult to develop the fragment into a drug.”

Although R2KD has already identified one promising new anti-cancer compound, the ICR team says it  can also be used to discover a much broader range of drugs.

"We are confident that this procedure will become part of the standard drug discovery workflow,” said Dr Liu.

“Any teams with the right equipment can use our method, so we hope it will benefit the wider drug discovery community.”

Before the R2KD test, it was only possible to qualify interactions between fragments and target proteins – giving an indication of whether they had occurred or not, but no clue about interaction strength. This lack of quantitative data forced researchers to spend valuable laboratory resources in ruling out weaker candidates later on in the drug development process, instead of focusing on the most viable compounds.

Professor Sven Hoelder, the head of the ICR’s Centre for Cancer Drug Discovery, said: “Our work has made a significant contribution to refining the (FBDD) process and maximising its efficiency.

“We believe (R2KD) will make NMR-based fragment drug discovery more accessible to research teams in academia and industry.”

 Figure an extract from the whitepaper 20 years of fragment-based discovery leads to success with “undruggable” targets authored for LGC by Joe Lackey PhD in 2023.