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

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.