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Mechanism-based inactivation of human aldehyde oxidase by erlotinib: Mechanistic insights from structural analogs and molecular docking
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Vijaya Saradhi Mettu,
Karl Austin-Muttitt,
Jonathan Mullins ,
Aik Jiang Lau
Molecular Pharmacology, Volume: 108, Issue: 1, Start page: 100097
Swansea University Authors:
Karl Austin-Muttitt, Jonathan Mullins
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DOI (Published version): 10.1016/j.molpha.2025.100097
Abstract
Aldehyde oxidase (AOX1) is a cytosolic molybdo-flavoenzyme that metabolizes azaheterocyclic drugs. Erlotinib and gefitinib are azaheterocyclic drugs. We deployed structural analogs to investigate the molecular interaction between these drugs and AOX1. Erlotinib, O-desmethylerlotinib, and O-didesmeth...
| Published in: | Molecular Pharmacology |
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| ISSN: | 0026-895X |
| Published: |
Elsevier BV
2026
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| Online Access: |
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| URI: | https://cronfa.swan.ac.uk/Record/cronfa71215 |
| Abstract: |
Aldehyde oxidase (AOX1) is a cytosolic molybdo-flavoenzyme that metabolizes azaheterocyclic drugs. Erlotinib and gefitinib are azaheterocyclic drugs. We deployed structural analogs to investigate the molecular interaction between these drugs and AOX1. Erlotinib, O-desmethylerlotinib, and O-didesmethylerlotinib, but not gefitinib, O-desmethylgefitinib, or O-desmorpholinopropylgefitinib, decreased carbazeran 4-oxidation by liver cytosol (human, rat, and mouse) and human recombinant AOX1. Erlotinib, O-desmethylerlotinib, and O-didesmethylerlotinib exhibited time- and concentration-dependent inactivation with unbound inactivation potency (KI,u) of 1.52, 4.41, and 1.67 μM, respectively. The inactivation was not reversed after dialysis, not protected by nucleophilic trapping agents or scavengers of reactive oxygen species, not affected by an oxidizing or reducing agent, but was attenuated by an alternative AOX1 substrate (O6-benzylguanine) and competitive AOX1 inhibitor (gefitinib). The terminal alkyne group of erlotinib was essential for AOX1 inactivation, as suggested by the findings for 3-vinylerlotinib (less potent inactivator) and tetrahydroerlotinib (no inactivation). Molecular docking results predicted covalent binding of erlotinib, O-desmethylerlotinib, and O-didesmethylerlotinib to the molybdenum cofactor. Adding a 4′-methyl group to erlotinib increased the inactivation potency but decreased inactivation efficiency, whereas blocking the C2-position of erlotinib with a hydroxy group or a methyl group decreased inactivation potency and efficiency, suggesting that the C2-position of erlotinib plays a role in AOX1 inactivation. In mice, erlotinib increased carbazeran (Aox substrate) and decreased 4-oxo-carbazeran (metabolite) levels in blood, liver, and kidneys. Overall, our study provides molecular insights into the mechanism-based inactivation of AOX1 by erlotinib, O-desmethylerlotinib, and O-didesmethylerlotinib and the irreversible AOX1 inactivation by erlotinib on the pharmacokinetics of AOX1-metabolized drugs. Significance Statement: This study shows that erlotinib and select metabolites are mechanism-based inactivators of AOX1, provides insights into the mechanism of the inactivation by deploying structural analogs and molecular docking, and demonstrates the in vivo impact on AOX1-mediated drug metabolism. |
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| Keywords: |
Aldehyde oxidase; Erlotinib; Structural analogs; Mechanism-based inactivation; Molecular docking; Pharmacokinetics |
| College: |
Faculty of Medicine, Health and Life Sciences |
| Funders: |
This research was supported in part by the Natural Sciences and Engineering Research Council of Canada (NSERC) [Grant RGPIN-2022-03342] and in part by the Singapore Ministry of Education and the Singapore Ministry of Health’s National Medical Research Council [Grant NMRC/BNIG/2044/2016]. The molecular docking was undertaken at the Supercomputing Wales research facility, Swansea University. |
| Issue: |
1 |
| Start Page: |
100097 |