High Throughput MS Scientist Merck, Hessen, Germany
Fragment based drug discovery is one of the tools in the toolbox of drug discovery approaches. Amongst them, covalent fragment screening can lead to viable chemical starting points with high potency and selectivity, prolonged duration of action with good pharmacokinetic profiles, and can even be applied to targets deemed less druggable. Covalent fragment screening is traditionally performed by crystallographic-, nuclear magnetic resonance- (NMR), and mass spectrometry- (MS) based methods. Crystallographic methods provide a chemical and structural basis of target-compound interaction allowing for further rational design and growth of the fragment starting point. NMR-based methods offer binding site elucidation, potential determination of binding modes, as well as being able to establish structure activity relationships. Liquid chromatography mass spectrometry (LC-MS) offers direct and unbiased measurement of target-compound interactions and can even specify compound binding down to a specific amino acid. While each of these methods have separate strengths, all three methods suffer from relatively low throughput, making it difficult to screen large fragment libraries. Matrix assisted laser desorption ionization (MALDI)-MS maintains the benefits unbiased analyses of LC-MS, albeit with a small penalty of more complex sample preparation. However, the speed benefits granted by MALDI—both in data acquisition as well as the coupling possibilities to high throughput automation systems—far outweigh any negatives, while also offering less complex data and low sample amount requirements. Here we present a MALDI-based workflow taking advantage of high throughput screening (HTS) automation equipment in combination with a high throughput focused MALDI and Genedata Screener software designed for large scale MS data analysis. Together, the workflow leads to increased throughput and automated analysis of covalent fragment screens.