Ranking Hits From Saturation Transfer Difference Nuclear Magnetic Resonance–Based Fragment Screening

Frontiers in Chemistry

Christoph Rademacher¹  Jonas Aretz¹ 

[1] Department of Biology, Chemistry, and Pharmacy, Freie Universität Berlin, Berlin, Germany;Department of Biomolecular Systems, Max Planck Institute of Colloids and Interfaces, Potsdam, Germany;

关键词: fragment-based drug discovery;    fragment-based drug design;    saturation transfer difference nuclear magnetic resonance spectroscopy;    STD NMR;    screening;   

DOI  :  10.3389/fchem.2019.00215

来源: DOAJ

【 摘 要 】

Fragment-based screening is an established route to identify low-molecular-weight molecules to generate high-affinity inhibitors in drug discovery. The affinities of these early hits from fragment screenings require a highly sensitive biophysical screening technique. Saturation transfer difference (STD) nuclear magnetic resonance (NMR) is one of the most popular methods owing to its high sensitivity for low-affinity ligands. It would be highly beneficial if rank-ordering of hits according to their affinity from an initial or counter-screen could be performed—a selection criterion found in the literature. We applied Complete Relaxation and Conformational Exchange Matrix (CORCEMA) theory adapted for saturation transfer (ST) measurements (CORCEMA-ST) calculations to predict STD NMR results from a large set of fragment/receptor pairs to investigate the boundaries under which the assumption holds true that a high STD effect can be applied to select for higher-affinity fragments. Overall, we come to the conclusion that this assumption is invalid.

【 授权许可】

Unknown