Structure-metabolism Relationships in AOX: Chemical Insights from a Large Database of Aza-aromatic and Amide Compounds

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2017 Apr 5

PMID 28373537

Citations 13

Authors

Susan Lepri

Martina Ceccarelli

Nicolo Milani

Sara Tortorella

Andrea Cucco

Aurora Valeri

Laura Goracci

Andreas Brink

Gabriele Cruciani

Affiliations

Soon will be listed here.

Abstract

Aldehyde oxidase (AOX) is a metabolic enzyme catalyzing the oxidation of aldehyde and aza-aromatic compounds and the hydrolysis of amides, moieties frequently shared by the majority of drugs. Despite its key role in human metabolism, to date only fragmentary information about the chemical features responsible for AOX susceptibility are reported and only "very local" structure-metabolism relationships based on a small number of similar compounds have been developed. This study reports a more comprehensive coverage of the chemical space of structures with a high risk of AOX phase I metabolism in humans. More than 270 compounds were studied to identify the site of metabolism and the metabolite(s). Both electronic [supported by density functional theory (DFT) calculations] and exposure effects were considered when rationalizing the structure-metabolism relationship.

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