Aldehyde Oxidase Mediated Metabolism in Drug-like Molecules: A Combined Computational and Experimental Study

J Med Chem. 2017 Apr 13;60(7):2973-2982. doi: 10.1021/acs.jmedchem.7b00019. Epub 2017 Mar 16.


Aldehyde oxidase (AOX) is an important drug-metabolizing enzyme. However, the current in vitro models for evaluating AOX metabolism are sometimes misleading, and preclinical animal models generally fail to predict human AOX-mediated metabolism. In this study, we report a combined computational and experimental investigation of drug-like molecules that are potential aldehyde oxidase substrates, of which multiple sites of metabolism (SOMs) mediated by AOX and their preferences for the reaction can be unambiguously identified. In addition, the proposed strategy was used to evaluate the metabolism of newly designed c-Met inhibitors, and a success switch-off of AOX metabolism was observed. Overall, this study provide useful information to guide lead optimization and drug discovery based on AOX-mediated metabolism.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aldehyde Oxidase / metabolism*
  • Drug Discovery
  • Humans
  • Kinetics
  • Models, Biological
  • Pharmaceutical Preparations / chemistry
  • Pharmaceutical Preparations / metabolism*
  • Proto-Oncogene Proteins c-met / antagonists & inhibitors
  • Species Specificity


  • Pharmaceutical Preparations
  • Aldehyde Oxidase
  • Proto-Oncogene Proteins c-met