Mechanism-based inactivation of human aldehyde oxidase by erlotinib: Mechanistic insights from structural analogs and molecular docking
Bibliographic record
Abstract
Aldehyde oxidase (AOX1) is a cytosolic molybdo-flavoenzyme that metabolizes azaheterocyclic drugs. Erlotinib and gefitinib are azaheterocyclic drugs. We deployed structural analogues 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 ( K I,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 ( O 6 -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 C 2 -position of erlotinib with a hydroxy group or a methyl group decreased inactivation potency and efficiency, suggesting that the C 2 -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.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".