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Perspectives on NMR in drug discovery: a technique comes of age

Nature Reviews Drug Discovery volume 7, pages 738–745 (2008)Cite this article

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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Figure 1: Overview of applications of NMR in drug discovery.

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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.

Author information

Authors and Affiliations

  1. Maurizio Pellecchia is at the Burnham Institute for Medical Research, La Jolla, 92037 California, USA.,

    Maurizio Pellecchia

  2. Ivano Bertini and Claudio Luchinat are at the Magnetic Resonance Center, The University of Florence, 50019 Sesto Fiorentino, Italy.,

    Ivano Bertini & Claudio Luchinat

  3. David Cowburn is at the New York Structural Biology Center, New York, 10027 New York, USA.,

    David Cowburn

  4. Claudio Dalvit is at the Experimental Therapeutics Programme, Centro Nacional de Investigaciones Oncológicas (CNIO), 28029 Madrid, Spain.,

    Claudio Dalvit

  5. Barcelona and Department of Organic Chemistry, Ernest Giralt is at the Institute for Research in Biomedicine, University of Barcelona, 08028 Barcelona, Spain.,

    Ernest Giralt

  6. Wolfgang Jahnke is at the Novartis Institute for BioMedical Research, 4002 Basel, Switzerland.,

    Wolfgang Jahnke

  7. Thomas L. James is at the School of Pharmacy, University of California at San Francisco, 94158 California, USA.,

    Thomas L. James

  8. Steve W. Homans is at the Institute of Molecular and Cellular Biology, University of Leeds, LS2 9JT UK.,

    Steve W. Homans

  9. Department Chemie, Horst Kessler is at the Center of Integrated Protein Science at the Technische Universität München, 85747 Munich, Germany.,

    Horst Kessler

  10. Bernd Meyer is at the Institute for Organic Chemistry University of Hamburg, 20146 Hamburg, Germany.,

    Bernd Meyer

  11. Hartmut Oschkinat is at the Forschungsinstitut für Molekulare Pharmakologie, Berlin 13125, Germany.,

    Hartmut Oschkinat

  12. Jeff Peng is at the University of Notre Dame, 46556 Indiana, USA.,

    Jeff Peng

  13. Harald Schwalbe is at the Center for Biomolecular Magnetic Resonance, 60438 Frankfurt, Germany.,

    Harald Schwalbe

  14. Gregg Siegal is at the Institute of Chemistry, Leiden University, 2300RA Leiden, The Netherlands.,

    Gregg Siegal

Authors
  1. Maurizio Pellecchia
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  2. Ivano Bertini
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  3. David Cowburn
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  4. Claudio Dalvit
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  5. Ernest Giralt
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  6. Wolfgang Jahnke
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  7. Thomas L. James
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  8. Steve W. Homans
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  9. Horst Kessler
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  10. Claudio Luchinat
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  11. Bernd Meyer
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  12. Hartmut Oschkinat
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  13. Jeff Peng
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  14. Harald Schwalbe
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  15. Gregg Siegal
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Corresponding author

Correspondence to Maurizio Pellecchia.

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Competing interests

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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FURTHER INFORMATION

Burnham Center for Chemical Genomics

The University of California at San Diego School of Pharmacy

The University of California at San Francisco School of Pharmacy

Burnham Institute for Medical Research, Graduate Programs in Molecular Medicine and Integrated and Applied Biosciences

Molecular Libraries Screening Centers Network initiative

NIAID's Antimicrobial Acquisition and Coordinating Facility

NCI's Developmental Therapeutics Program

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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