NMR in drug discovery: A practical guide to identification and validation of ligands interacting with biological macromolecules

Prog Nucl Magn Reson Spectrosc. 2016 Nov;97:82-125. doi: 10.1016/j.pnmrs.2016.09.001. Epub 2016 Sep 30.


Protein-ligand interactions are at the heart of drug discovery research. NMR spectroscopy is an excellent technology to identify and validate protein-ligand interactions. A plethora of NMR methods are available which are powerful, robust and information-rich, but also have pitfalls and limitations. In this review, we will focus on how to choose between different experiments, and assess their strengths and liabilities. We introduce the concept of the validation cross, which helps to categorize experiments according to their information content and to simplify the choice of the right experiment in order to address a specific question. Additionally, we will provide the framework for drawing correct conclusions from experimental results in order to accurately evaluate such interactions. Out of scope for this review are methods for subsequent characterization of the interaction such as quantitative KD determination, binding mode analysis, or structure determination.

Keywords: Drug discovery; Fragment-based screening; Protein-ligand Interactions; Validation.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Binding Sites
  • Biophysical Phenomena
  • Drug Discovery / methods*
  • Humans
  • Ligands*
  • Nuclear Magnetic Resonance, Biomolecular / methods*
  • Pharmacokinetics
  • Proteins / chemistry*


  • Ligands
  • Proteins