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Solid-state NMR in drug design and discovery for membrane-embedded targets

Nature Reviews Drug Discovery volume 4, pages 555–568 (2005)Cite this article

Key Points

  • Drug discovery for membrane targets will be a major focus for the foreseeable future.

  • However, the lack of essential high-resolution structural details at the molecular level, and the well-acknowledged technical difficulties that are associated with the crystallography of membrane proteins, have hampered the development of rational drug discovery for membrane targets.

  • NMR is a tool that is used to derive local (magnetic) information at the atomic level and is, therefore, limited by complexity in large molecules.

  • However, defining ligand–protein interactions does, fortuitously, require local information and so NMR comes into its own. Observing drugs at their membrane-embedded target directly is an important challenge that solid-state NMR is now addressing

  • This review describes the application of solid-state NMR for detecting ligands at their site of action, resolving drug structures at their site of action, defining target binding sites, resolving ligand orientation, resolving bound drug dynamics and assessing drug partitioning.

Abstract

Observing drugs and ligands at their site of action in membrane proteins is now possible through the use of a development in biomolecular NMR spectroscopy known as solid-state NMR. Even large, functionally active complexes are being examined using this method, with structural details being resolved at super-high subnanometre resolution. This is supplemented by detailed dynamic and electronic information about the surrounding ligand environment, and gives surprising new insights into the way in which ligands bind, which can aid drug design.

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Figure 1: Solid-state NMR in drug discovery.
Figure 2: Determining Kd for ligands.
Figure 3: Resolving drug structures at the site of action.
Figure 4: Identifying bound ligand environment.
Figure 5: Differential dynamics of bound ligands.

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Acknowledgements

The work described here from this group was supported by the European Union (EU), the Medical Research Council (MRC) UK, the Biotechnology and Biological Sciences Research Council (BBSRC), the Engineering and Physical Sciences Research Council (EPSRC) and the Higher Education Funding Council for England (HEFCE), with commercial support from Varian Inc. and Magnex Scientific Ltd., GlaxoSmithKline, Syngenta, Nestec and the Cheil Jedang Corporation.

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Authors and Affiliations

  1. Biochemistry Department, Biomembrane Structure Unit, University of Oxford, Oxford, OX1 3QU, UK

    Anthony Watts

  2. Biological Solid State NMR Facility, Rutherford Appleton Laboratories, Chilton, OX10 0QX, UK

    Anthony Watts

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DATABASES

OMIM

Alzheimer's disease

attention-deficit/hyperactivity disorder

gastro-oesophageal reflux disease

Tourette's syndrome

Parkinson's disease

schizophrenia

Glossary

TUMBLING

A term used to describe molecules moving freely in solution and reorientating themselves quickly with respect to any given point.

CHEMICAL SHIFT

The chemical shift of a particular nucleus is a measure of the dependence of the resonance frequency of the nucleus on its chemical environment.

ASSIGNMENT

The process of attributing a resonance in an NMR spectrum to a particular nucleus in a molecule.

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Watts, A. Solid-state NMR in drug design and discovery for membrane-embedded targets. Nat Rev Drug Discov 4, 555–568 (2005). https://doi.org/10.1038/nrd1773

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