1D NMR WaterLOGSY as an efficient method for fragment-based lead discovery. (1st January 2019)

• Record Type: Journal Article
• Authors: Raingeval, Claire; Cala, Olivier; Brion, Béatrice; Le Borgne, Marc; Hubbard, Roderick Eliot; Krimm, Isabelle
• Is Part Of: Journal of enzyme inhibition and medicinal chemistry. Volume 34:Number 1(2019)
• Page Start: 1218
• Page End: 1225
• Publication Date: 2019-01-01
• Subjects: WaterLOGSY -- solvent-exposed -- saturation transfer difference -- binding mode -- fragment-based lead discovery; Enzyme inhibitors -- Periodicals; Enzyme Inhibitors -- periodicals; Biochemistry -- periodicals; 572.7
• DOI: 10.1080/14756366.2019.1636235
• Languages: English
• ISSNs: 1475-6366

Abstract

Abstract: WaterLOGSY is a sensitive ligand-observed NMR experiment for detection of interaction between a ligand and a protein and is now well-established as a screening technique for fragment-based lead discovery. Here we develop and assess a protocol to derive ligand epitope mapping from WaterLOGSY data and demonstrate its general applicability in studies of fragment-sized ligands binding to six different proteins (glycogen phosphorylase, protein peroxiredoxin 5, Bcl-xL, Mcl-1, HSP90, and human serum albumin). We compare the WaterLOGSY results to those obtained from the more widely used saturation transfer difference experiments and to the 3D structures of the complexes when available. In addition, we evaluate the impact of ligand labile protons on the WaterLOGSY data. Our results demonstrate that the WaterLOGSY experiment can be used as an additional confirmation of the binding mode of a ligand to a protein.