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Introduction: Given the rising trend in medicinal chemistry strategy to reduce cytochrome P450-dependent metabolism, aldehyde oxidase (AOX) has recently gained increased attention in drug discovery programs and the number of drug candidates that are metabolized by AOX is steadily growing. Areas covered: Despite the emerging importance of AOX in drug discovery, there are certain major recognized problems associated with AOX-mediated metabolism of drugs. Intra- and inter-species variations in AOX activity, the lack of reliable and predictive animal models using the common experimental animals, and failure in the predictions of in vivo metabolic activity of AOX using traditional in vitro methods are among these issues that are covered in this article. A comprehensive review of computational human AOX (hAOX) related studies are also provided. Expert opinion: Following the recent progress in the stem cell field, the authors recommend the application of organoids technology as an effective tool to solve the fundamental problems associated with the evaluation of AOX in drug discovery. The recent success in resolving the hAOX crystal structure can too be another valuable data source for the study of AOX-catalyzed metabolism of new drug candidates, using computer-aided drug discovery methods.

Aldehyde oxidase (AOX), a highly conserved molybdoflavoenzyme in mammal cytoplasm, has broad substrate specificity and ability to catalyze the oxidation of aldehydes and nitrogen, oxygen-containing heterocyclic rings. AOX was found to widely distribute with the individual differences in vivo and plays an important role in phase I metabolism of drugs and xenobiotics. The biological characteristics of AOX and its contributions in drug metabolism are introduced briefly in this review.

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.

Aldehyde oxidases are molybdoflavoenzymes with broad substrate specificity, oxidizing different types of aldehydes, and heterocyclic rings. The physiological function of aldehyde oxidases is largely unknown, although the enzymes play an important role in the metabolism of numerous compounds of medicinal and toxicological interest, as they oxidize a wide range of aldehydes and heterocyclic compounds. In this article, we review the significance of aldehyde oxidases for the design and development of new drugs and discuss associated problems. These include species-specific differences in the complement of isoenzymes synthesized and general difficulties in studying the enzymatic characteristics of purified or recombinant aldehyde oxidases. We highlight the potential offered by human aldehyde oxidase targeting for the development of new pharmacological agents, limiting our attention to the realms of antiobesity and anti-cancer drugs. The last point is discussed in the context of the design of novel anticancer drugs, selectively activated or inactivated by this enzyme, with the final aim of achieving organ and/or tumor selectivity.