Structure-based ligand design to overcome CYP inhibition in drug discovery projects

Drug Discov Today. 2014 Jul;19(7):905-11. doi: 10.1016/j.drudis.2014.03.012. Epub 2014 Mar 16.


Cytochrome P450 (CYP) enzymes are key players in xenobiotic metabolism, and inhibition of CYPs can therefore result in unwanted drug-drug interactions. Within drug discovery, CYP inhibition can cause delays in the progression of candidate drugs, or even premature closure of projects. During the past decade, a massive effort in the pharmaceutical industry and academic research has produced a wealth of structural information in the CYP field. In this short review, we will describe how structure-based approaches can be used in the pharmaceutical industry to work away from CYP inhibition, with a focus on the opportunities and challenges. We will show two examples from our own work where structural information on CYP2C9 and CYP3A4 inhibitor complexes have been successfully exploited in ongoing drug discovery projects.

Publication types

  • Review

MeSH terms

  • Animals
  • Cytochrome P-450 Enzyme Inhibitors / chemistry*
  • Cytochrome P-450 Enzyme Inhibitors / metabolism
  • Cytochrome P-450 Enzyme Inhibitors / pharmacology
  • Cytochrome P-450 Enzyme System / chemistry*
  • Cytochrome P-450 Enzyme System / metabolism
  • Drug Discovery / methods*
  • Humans
  • Ligands
  • Protein Structure, Secondary
  • Structure-Activity Relationship


  • Cytochrome P-450 Enzyme Inhibitors
  • Ligands
  • Cytochrome P-450 Enzyme System