NMR approaches in structure-based lead discovery: recent developments and new frontiers for targeting multi-protein complexes.

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Dias, David M 
Ciulli, Alessio 

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.


This is the final version. It was first published by Elsevier at http://www.sciencedirect.com/science/article/pii/S007961071400087X.

Hit-to-lead optimization, Multi-protein complexes, NMR fragment screening, Protein expression, Protein–protein interactions, Structure-based lead discovery, Drug Discovery, Ligands, Magnetic Resonance Spectroscopy, Proteins
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Prog Biophys Mol Biol
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Elsevier BV
The authors are very grateful to the organizations that funded their research: the UK Biotechnology and Biological Sciences Research Council (BBSRC, grants BB/J001201/1 and David Phillips Fellowship BB/G023123/1 to A.C.), the European Research Council (ERC-2012-StG-311460 DrugE3CRLs, Starting Grant to A.C.) the European Commission (Bio-NMR, Project 261863), and the Fundação para a Ciência e a Tecnologia (FCT, SFRH/BD/81735/2011 Studentship to D.M.D.).