Characterising the Irreversible: Using Biophysics to Enable Covalent Drug Discovery

The popularity of covalently active molecules for use as therapeutics has seen a resurgence in recent years and has led to a number of advances in both the identification of hits and their development into therapeutically active molecules. There still, however, has been a gap in the assessment of covalently active molecules, which has typically been expensive and slow to remedy. At Sygnature Discovery, we have developed a biophysical assay platform to provide detailed kinetic characterisation of these molecules to support their development throughout the discovery pipeline.

It is well known that there are a significant number of covalently active drugs on the market, whether they were intentionally designed as such or not. Despite this, assay platforms to enable their development are typically lacking, even when the characterisation of covalent molecules is critical in managing both their benefits and risks. At Sygnature, we use surface plasmon resonance (SPR) to support large sections of the drug discovery pipeline, from the initial characterisation hits from screening campaigns, through warhead selection and tuning, to the in-depth analysis of candidate molecules for the selection of optimal properties. SPR is uniquely suited to this process as a time-controlled and highly sensitive approach, which can be tailored to achieve good throughput, even with potent irreversible binders. This allows us to support medicinal chemistry efforts on a range of fast-paced and challenging discovery projects against a wide selection of targets.