Computer‐aided drug design of small molecule inhibitors of the ERCC1‐XPF protein–protein interaction
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
Abstract The heterodimer of DNA excision repair protein ERCC‐1 and DNA repair endonuclease XPF (ERCC1‐XPF) is a 5′–3′ structure‐specific endonuclease essential for the nucleotide excision repair (NER) pathway, and it is also involved in other DNA repair pathways. In cancer cells, ERCC1‐XPF plays a central role in repairing DNA damage induced by chemotherapeutics including platinum‐based and cross‐linking agents; thus, its inhibition is a promising strategy to enhance the effect of these therapies. In this study, we rationally modified the structure of F06, a small molecule inhibitor of the ERCC1‐XPF interaction ( Molecular Pharmacology , 84 , 2013 and 12), to improve its binding to the target. We followed a multi‐step computational approach to investigate potential modification sites of F06, rationally design and rank a library of analogues, and identify candidates for chemical synthesis and in vitro testing. Our top compound, B5 , showed an improved half‐maximum inhibitory concentration (IC 50 ) value of 0.49 µM for the inhibition of ERCC1‐XPF endonuclease activit, and lays the foundation for further testing and optimization. Also, the computational approach reported here can be used to develop DNA repair inhibitors targeting the ERCC1‐XPF complex.
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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 | 0.001 | 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