title: NMR approaches in structure-based lead discovery: recent developments and new frontiers for targeting multi-protein complexes.
abstract: Nuclear magnetic resonance (NMR) spectroscopy is a pivotal method for structure-based and fragment-based lead discovery because it is one of the most robust techniques to provide information on protein structure, dynamics and interaction at an atomic level in solution. Nowadays, in most ligand screening cascades, NMR-based methods are applied to identify and structurally validate small molecule binding. These can be high-throughput and are often used synergistically with other biophysical assays. Here, we describe current state-of-the-art in the portfolio of available NMR-based experiments that are used to aid early-stage lead discovery. We then focus on multi-protein complexes as targets and how NMR spectroscopy allows studying of interactions within the high molecular weight assemblies that make up a vast fraction of the yet untargeted proteome. Finally, we give our perspective on how currently available methods could build an improved strategy for drug discovery against such challenging targets.
authors.affiliation: Department of Chemistry, University of Cambridge, Cambridge, CB2 1EW, UK.
authors.forename: David M
authors.initials: DM
authors.lastname: Dias
authors.affiliation: College of Life Sciences, Division of Biological Chemistry and Drug Discovery, University of Dundee, Dow Street, DD1 5EH, Dundee, UK. Electronic address: a.ciulli@dundee.ac.uk.
authors.forename: Alessio
authors.initials: A
authors.lastname: Ciulli
mesh_terms: D055808:Drug Discovery / Q000379:methods*; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy / Q000379:methods*; D011506:Proteins / Q000737:chemistry* / Q000378:metabolism
chemical_list: D008024:Ligands; D011506:Proteins
keywords: Hit-to-lead optimization; Multi-protein complexes; NMR fragment screening; Protein expression; Protein–protein interactions; Structure-based lead discovery