Abstract
In the past decade, the potential of harnessing the ability of nuclear magnetic resonance (NMR) spectroscopy to monitor intermolecular interactions as a tool for drug discovery has been increasingly appreciated in academia and industry. In this Perspective, we highlight some of the major applications of NMR in drug discovery, focusing on hit and lead generation, and provide a critical analysis of its current and potential utility.
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Acknowledgements
This article is based on a document drafted by I. B., C. L. and M. P., during the workshop 'Perspectives of NMR in Drug Discovery' held in Florence April 2007. Financial support by the NMR-Life Coordination Action LSHG-CT-2005-018,758, by Ente CR Firenze and by MCYT-FEDER (Bio2005-00295) is gratefully acknowledged. We thank M. Fragai and C. Lipinski for suggestions and comments. We also thank L. Slivka for careful assistance in the preparation of the manuscript.
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B.M. is co-inventor of a patent that covers Saturation Transfer Difference (STD) NMR. G. S. owns more than 5% of ZoBio, a fragment-based drug discovery company.
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Glossary
- Druggability
-
The ability of a target to be modulated by a lead candidate that has the requisite physicochemical and absorption, distribution, metabolism and excretion properties for development as a drug candidate.
- Drug-like
-
Sharing certain characteristics — such as size, shape and solubility in water and organic solvents — with other molecules that act as drugs.
- Hit
-
A compound that satisfies an initial set of criteria (for example, minimum potency and solubility), but which requires elaboration or validation through further detailed analysis of performance or additional iterations to become a lead.
- Hot spots
-
Compact, centralized regions of residues at a protein–protein interface that are crucial for the affinity of the interaction.
- Lipinski's “Rule of Five”
-
This identifies several key properties that should be considered for small molecules that are intended to be orally administered. These properties are: molecular mass <500 Da; number of hydrogen-bond donors <5; number of hydrogen-bond acceptors <10; calculated octanol–water partition coefficient (an indication of the ability of a molecules to cross biological membranes) <5.
- Relaxation rate
-
The terms longitudinal and transverse relaxation rates describe the rates at which nuclear magnetization returns to the equilibrium after perturbation in a non-equilibrium state.
- NMR 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.
- Nuclear Overhauser effect (NOE)
-
Change in the intensity of the NMR signal, which is caused by through-space dipole–dipole coupling. Upper distance constraints obtained from 1H–1H NOEs are used to determine the structure of biological macromolecules.
- Nuclear spin-relaxation
-
This term describes several physical processes by which nuclear magnetization that is perturbed in a non-equilibrium state returns to equilibrium. Nuclear spin relaxation rates depend on the overall rotational correlation time of the molecule and on the number and nature of interacting spins.
- Paramagnetically labelled
-
Nuclear spin relaxation rates are enhanced for a given nucleus when it is in close proximity to a molecule containing an electron spin (a paramagnetic molecule). Labelling a reference ligand or a target with a paramagnetic molecule can provide spatial information on the binding of a test ligand.
- Pharmacophore
-
The steric and electronic features of a ligand that are necessary to ensure optimal interactions with a biological target structure and to trigger (or to block) its biological response.
- Saturated ligand
-
NMR relaxation phenomena on the nuclei of a bound ligand result in the attenuation of its NMR signal intensities. When the signal is nearly completely suppressed, the ligand is said to be saturated.
- Selective irradiation
-
Application of radio frequency energy at a particular narrow frequency. This will cause the selective saturation of the resonance lines in the spectrum of nuclei that resonate at that frequency.
- Solid-state NMR
-
NMR measurement of the magnetic properties of nuclei in solid samples rather than of samples in solution. They are characterized by anisotropic and directionally dependent interactions that can be useful to obtain structural information.
- Two-dimensional correlation spectra
-
NMR experiments that exploit nuclear coupling to correlate the chemical shifts of protons with other NMR-active nuclei, most often 13C or 15N.
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Pellecchia, M., Bertini, I., Cowburn, D. et al. Perspectives on NMR in drug discovery: a technique comes of age. Nat Rev Drug Discov 7, 738–745 (2008). https://doi.org/10.1038/nrd2606
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DOI: https://doi.org/10.1038/nrd2606
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