Investigating a Potential Hotspot for the Interaction of a Group of Corrector Compounds on F508del-CFTR
Bibliographic record
Abstract
Cystic fibrosis (CF) is a rare hereditary disease that primarily impacts the lungs. CF is a result of mutant cystic fibrosis transmembrane conductance regulator (CFTR) protein being synthesized, where F508del is the most common variant. Several small molecules (modulators) can help rescue mutant CFTR, including correctors (eg. VX-445), which restore CFTR folding and processing. Previous cryo-EM work identified the interaction site for VX-445 on F508del-CFTR. It is not currently known whether four novel Galapagos/AbbVie correctors bind the same site as VX-445 on CFTR. Using biochemical and functional assays to evaluate the modulators’ capacity to correct VX-445 binding site mutants, I found that the novel corrector X990 shares a mechanistic action with VX-445. These results support the idea that AbbVie correctors bind CFTR at the same site, which is therefore a hotspot for type III corrector interaction, with future use as a tool for screening other novel, potentially more effective, modulators.
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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 | 0.000 |
| 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) | 0.007 | 0.001 |
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".