Development of a General Strategy to Access Bisubstrate Inhibitors of Acetyltransferase Enzymes In Vivo
Bibliographic record
Abstract
The growing antibiotic resistance crisis makes the development of new antibiotic drugs crucial. Bisubstrate enzymes are key components of many biosynthetic pathways. Covalently linking the two substrates can generate a potent inhibitor, but they are incapable of crossing cell membranes. This project set out to develop a strategy to generate bisubstrate inhibitors for acetyltransferases in vivo. The enzyme targeted was M. tuberculosis GlmU which uses GlcN-1P and AcCoA to make the key metabolite UDP-GlcNAc. The goal of this project was to assess whether GlmU could catalyze the formation of its own potent bisubstrate inhibitor from a GlcNAc-1-phosphate electrophile and CoA. GlcN bearing acryloyl and chloroacetamide functional groups were synthesized and assessed in vitro with GlmU. Unfortunately, no evidence of bisubstrate formation catalyzed by GlmU was obtained for either substrate. The synthesis of a third substrate based on a thioester was explored and further work is necessary to complete this synthesis.
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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) | 0.001 | 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 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 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".