Insight into the Mechanism of 17β-Hydroxysteroid Dehydrogenase Type 3 Inhibition by the Androsterone Derivative RM-532-105
Bibliographic record
Abstract
Background: The last step in the production of androgen testosterone from 4-androstene- 3,17-dione (4-dione) in testis involves the 17β-hydroxysteroid dehydrogenase type 3 (17β-HSD3). Blocking this microsomal enzyme with an inhibitor would lower the level of testosterone and, consequently, could be an approach for the treatment of androgen-dependent diseases. RM-532-105 was developed as a steroidal inhibitor of 17β-HSD3, but its mechanism of action is not yet known. Objective: To identify potential binding sites of the 17β-HSD3 substrate 4-dione, cofactor NADPH, as well as inhibitor RM-532-105. Methods: Since there is no crystal structure of 17β-HSD3 available, complexed or not with a ligand, a homology model was prepared followed by molecular docking, and enzymatic assay experiments were performed. Results: Transfected LNCaP prostate cancer cells were used as a source of 17β-HSD3 activity for the transformation of 4-dione into testosterone in the presence of varying concentrations of a substrate, a cofactor or an inhibitor. Molecular modeling experiments and enzymatic assays with these cells suggest a competitive action of RM-532-105 with the cofactor and a non-competitive action with the substrate 4-dione. Conclusion: These results allow the selection of one inhibitor orientation in the enzyme binding site, from the two possibilities predicted by the docking experiments, and appear to be in agreement with previous structure-activity relationships.
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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".