Mechanistic evidence from classical molecular dynamics and metadynamics revealed the mechanism of resistance to 4-hydroxy tamoxifen in estrogen receptor alpha Y537S mutant
Why this work is in the frame
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Bibliographic record
Abstract
Small molecule antagonists that bind to the ligand-binding domain (LBD) of estrogen receptor alpha (ERα) are effective in treating ERα-positive breast cancer patients. However, acquired treatment resistance is observed in the presence of somatic mutations in LBD of ERα. Y537S is the most aggressive mutation, causing constitutive activity of ERα in the absence of ligand and reducing the affinity and sensitivity of certain antagonists such as 4-hydroxy tamoxifen (4-OHT). To better understand the mechanism of resistance to 4-OHT, we performed a comparative study of wild-type and Y537S mutant ERα in complex with 4-OHT using classical molecular dynamics and metadynamics. The results of this study indicated that Helix 12 (H12) disruption is a typical allosteric effect of 4-OHT, allowing the receptor to maintain an antagonistic conformation. The Y537S mutation induces the loss of this effect by stabilising H12 through the newly formed H-bond between E380 and S537, thereby strengthening H12 to adopt an agonistic conformation even when 4-OHT is bound. The obtained results and the approaches applied in this study could be used as proof of principle for discovering more potent ERα inhibitors to overcome the endocrine resistance.
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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 | 0.001 | 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 it