d-Glucosylated Derivatives of Isofagomine and Noeuromycin and Their Potential as Inhibitors of ß-Glycoside Hydrolases
Bibliographic record
Abstract
While isofagomine and noeuromycin have previously been demonstrated to be effective inhibitors of a range of exo-acting glycosidases, they are usually only very weak inhibitors of endo-glycosidases. However, the disaccharide-like 3- and 4-O-ß-d-glucopyranosylisofagomines have proven to be strong inhibitors of these endo-acting enzymes that utilize multiple sub-sites. In an attempt to emulate these successes, we have prepared 3- and 4-O-ß-d-glucopyranosylnoeuromycin, the former by a selective glycosylation (at O2) of benzyl 4-C-cyano-4-deoxy-a-d-arabinoside (also leading to another synthesis of 3-O-ß-d-glucopyranosylisofagomine), the latter by a non-selective glycosylation of benzyl 4-O-allyl-ß-l-xyloside with subsequent introduction of the required nitrile group (also leading to another synthesis of 4-O-ß-d-glucopyranosylisofagomine). 3-O-ß-d-Glucopyranosylnoeuromycin was evaluated as an inhibitor of a family 26 lichenase from Clostridium thermocellum, and 4-O-ß-d-glucopyranosylnoeuromycin as an inhibitor of both a family 5 endo-glucanase from Bacillus agaradhaerans and a family 10 endo-xylanase from Cellulomonas fimi. We also report X-ray structural investigations of 3- and 4-O-ß-d-glucopyranosylnoeuromycin in complex with the family 26 and family 5 ß-glycoside hydrolases, respectively. The two d-glucosylated noeuromycins were indeed able to harness the additional binding energy from the sub-sites of their endo-glycoside hydrolase targets, and were thus excellent inhibitors (in the nanomolar range), binding as expected in the –1 and –2 sub-sites of the enzymes.
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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) | 0.001 | 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".