Aldehyde oxidase and its importance in novel drug discovery: present and future challenges

Abstract

Introduction: Aldehyde oxidases (AOXs) are molybdo-flavoenzymes that oxidize aromatic aldehydes into the corresponding carboxylic acids and heterocycles into hydroxylated derivatives. AOXs have broad substrate specificity and are present in the liver of humans and many experimental animals. These enzymes play an important role in Phase I metabolism of drugs and xenobiotics of toxicological interest.Areas covered: Preclinical studies on the AOX-dependent metabolism of new drug candidates are problematic. Furthermore, there is a general lack of reliable in silico methodologies to predict whether a new organic molecule is an AOX substrate. In vitro systems, for the design of high- or medium-throughput screening tests, to identify AOX substrates have many limitations. In vivo studies on AOX-dependent metabolism in animal models, on the other hand, are difficult because the complement of liver AOXs in humans and popular experimental animals is different. The authors discuss the possible ways to overcome all these problems.Expert opinion: The significance of AOXs as drug-metabolizing enzymes is increasing, as the current strategies of organic synthesis designed to avoid cytochrome P450 (CYP450)-dependent metabolism tend to enrich for new chemical structures efficiently oxidized by these enzymes. There is need for reliable methods to screen for, predict, and validate AOX-dependent metabolism of new drug candidates.