Virtual screening using covalent docking to find activators for G245S mutant p53
Bibliographic record
Abstract
TP53 is the most mutated gene in all cancers. The mutant protein also accumulates in cells. The high frequency of p53 mutations makes the protein a promising target for anti-cancer therapy. Only a few molecules have been found, using in vitro screening, to reactivate the mutant protein. APR-246 is currently the most successful mutant p53 activator, which reactivates the transcriptional activity of p53 by covalently binding to C124 of the protein. We have recently created in silico models of G245S-mp53 in its apo and DNA-bound forms. In this paper we further report on our in silico screening for potential activators of G245S-mp53. We filtered the ZINC15 database (13 million compounds) to only include drug-like molecules with moderate to standard reactivity. Our filtered database of 130,000 compounds was screened using the DOCKTITE protocol in the Molecular Operating Environment software. We performed covalent docking at C124 of G245S-mp53 to identify potential activators of the mutant protein. The docked compounds were ranked using a consensus scoring approach. We also used ADMET Predictor™ to predict pharmacokinetics and the possible toxicities of the compounds. Our screening procedure has identified compounds, mostly thiosemicarbazones and halo-carbonyls, with the best potential as G245S-mp53 activators, which are described in this work. Based on its binding scores and ADMET risk score, compound 2 is likely to have the best potential as a G245S-mp53 activator compared to the other top hits.
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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 | 0.001 | 0.001 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.002 | 0.001 |
| Bibliometrics | 0.001 | 0.002 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.003 | 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".