Mechanistic evidence from classical molecular dynamics and metadynamics revealed the mechanism of resistance to 4-hydroxy tamoxifen in estrogen receptor alpha Y537S mutant
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.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.001 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.001 | 0.001 |
| Scholarly communication | 0.000 | 0.001 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 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 source (direct Gemma or distilled Codex), 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".