Molecular Initiating Events of Bisphenols on Androgen Receptor-Mediated Pathways Provide Guidelines for <i>in Silico</i> Screening and Design of Substitute Compounds
Why this work is in the frame
A frame that forgets how it found something cannot be audited. These are the routes that admitted this work.
Bibliographic record
Abstract
Bisphenols (BPs) have the potential to interfere with the androgen receptor (AR). However, in silico screening and substitute design were difficult because little was known about the mechanisms by which BPs interfere with AR-mediated molecular initiating events (MIEs). Here, the AR disrupting effects and associated mechanisms of 15 BPs were evaluated by in vitro assays and molecular dynamics simulations. AR-mediated MIEs, including ligand–receptor interactions and coregulator recruitment, might determine active versus inactive and agonist versus antagonist activities of BPs, respectively. Bisphenol E (BPE), BPF, and BPS with no binding effects were inactive, while all other BPs were AR antagonists. On the basis of their coregulator recruitment patterns and repositioning of helix 12, BPBP, BPC, and BPPH were passive antagonists that blocked coregulator recruitment, and their anti-androgenic potencies were correlated with ligand–receptor interactions; others were active antagonists that recruited corepressors, and their anti-androgenic potencies were correlated with ligand–receptor–corepressor interactions. A new method was developed for MIE-based in silico qualitative and quantitative evaluations of the potential of BPs to disrupt AR-mediated pathways, by which safer BPA substitutes with smaller and less hydrophobic connecting groups could be designed. The MIE-based in silico methods can be used to screen a wider range of chemicals and to design better substitutes.
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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 | 0.001 |
| 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