Review Article | Published:

Biophysics in drug discovery: impact, challenges and opportunities

Nature Reviews Drug Discovery volume 15, pages 679698 (2016) | Download Citation

Abstract

Over the past 25 years, biophysical technologies such as X-ray crystallography, nuclear magnetic resonance spectroscopy, surface plasmon resonance spectroscopy and isothermal titration calorimetry have become key components of drug discovery platforms in many pharmaceutical companies and academic laboratories. There have been great improvements in the speed, sensitivity and range of possible measurements, providing high-resolution mechanistic, kinetic, thermodynamic and structural information on compound–target interactions. This Review provides a framework to understand this evolution by describing the key biophysical methods, the information they can provide and the ways in which they can be applied at different stages of the drug discovery process. We also discuss the challenges for current technologies and future opportunities to use biophysical methods to solve drug discovery problems.

Key points

  • The rapid development of sensitive biophysical methods is transforming drug discovery by providing early profiling of compound properties and insights into mechanisms of action.

  • Biophysical methods are used extensively in hit finding (fragment-based screening and high-throughput screening), hit validation, in depth characterization of compound binding and lead optimization.

  • A growing application of biophysical methods is to understand the relationship between the kinetics of binding, mode of action, and molecular structures and interactions. This has had substantial impact on recognizing the importance of binding kinetics and residence time for therapeutic action.

  • Additional information derived from biophysical methods ranges from protein quality control, quantitative binding data, and determination of ligand–target complex structures to complex mode-of-action studies.

  • The efficient use of these methods requires experience in experimental design and data analysis, and a strategic combination of orthogonal methods.

  • Newly emerging technologies such as cryo-electron microscropy (cryo-EM) for high-resolution determination of massive biological structures and more rapid methods for the characterization of binding kinetics and thermodynamics will further reinforce the importance of biophysics in drug discovery.

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Author notes

    • Michael Hennig

    Present address: leadXpro AG, PARK INNOVAARE, CH-5234 Villigen, Switzerland.

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  1. NovAliX, Boulevard Sébastien Brant, 67405 Illkirch Cedex, France.

    • Jean-Paul Renaud
  2. Institut de Génétique et Biologie Moléculaire et Cellulaire, CNRS UMR7104/INSERM U964/Université de Strasbourg, 1 rue Laurent Fries - BP10142, 67404 Illkirch Cedex, France.

    • Jean-Paul Renaud
  3. RiboStruct, 15 rue Neuve, 67540 Ostwald, France.

    • Jean-Paul Renaud
  4. GlaxoSmithKline R&D, Gunnels Wood Road, Stevenage, SG1 2NY, UK.

    • Chun-wa Chung
  5. Department of Chemistry — BMC and Science for Life Laboratory, Drug Discovery & Development Platform, Uppsala University, SE-751 05 Uppsala, Sweden.

    • U. Helena Danielson
  6. Beactica AB, Uppsala Business Park, 754 50 Uppsala, Sweden.

    • U. Helena Danielson
  7. Bayer Pharma AG, Müllerstrasse 178, 13353 Berlin, Germany.

    • Ursula Egner
  8. Hoffmann-La Roche Ltd, Grenzacherstrasse 124, 4070 Basel, Switzerland.

    • Michael Hennig
  9. University of York, Heslington, York, YO10 5DD, UK.

    • Roderick E. Hubbard
  10. Vernalis (R&D), Granta Park, Cambridge, CB21 6GB, UK.

    • Roderick E. Hubbard
  11. Boehringer Ingelheim GmbH & Co. KG, Birkendorfer Strasse 65, 88400 Biberach, Germany.

    • Herbert Nar

Authors

  1. Search for Jean-Paul Renaud in:

  2. Search for Chun-wa Chung in:

  3. Search for U. Helena Danielson in:

  4. Search for Ursula Egner in:

  5. Search for Michael Hennig in:

  6. Search for Roderick E. Hubbard in:

  7. Search for Herbert Nar in:

Competing interests

J.P.R. is a co-founder and a shareholder of NovAliX.

Corresponding authors

Correspondence to Jean-Paul Renaud or Chun-wa Chung or U. Helena Danielson or Ursula Egner or Michael Hennig or Roderick E. Hubbard or Herbert Nar.

About this article

Publication history

Published

DOI

https://doi.org/10.1038/nrd.2016.123

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