Fragment-based Drug Design Using NMR Methods

Abstract

Fragment-based drug design (FBDD) has evolved from a novel approach in the search of new hits to a valuable alternative to high-throughput screening (HTS) campaigns of many pharmaceutical companies. The increasing relevance of FBDD in the drug discovery area has been concomitant with the implementation of biophysical techniques used for the detection of weak inhibitors. In particular, NMR presents clear advantages over other techniques used in drug discovery as it can be used in the 3-D characterization of protein targets and protein–ligand complexes, as well as in the hit identification and lead optimization phases. Herein, we review the potential of FBDD by NMR using either target- or ligand-based methods in the discovery of novel fragment blocks against pharmaceutically relevant protein targets, and the different follow-up design strategies used to convert a fragment hit into a lead. Keywords: fragment-based screening; high-throughput screening; NMR spectroscopy; druggability; library design; fragment prioritization; fragment optimization; clinical candidate; drug development