Transition-State Mimicry by Glycosidase Inhibitors: A Critical Kinetic Analysis
Bibliographic record
Abstract
A considerable effort has been invested in the design and synthesis of transition-state analogue inhibitors of glycosidases, particularly with respect to their potential as therapeutics. However, their characterization as transition-state mimics is generally based only upon their high affinity. To provide a quantitative evaluation of the mimicry afforded by two commonly used classes of inhibitors, a set of 10 active site mutants of the Cellulomonas fimi xylanase Cex was generated, and kinetic parameters for substrate hydrolysis as well as for inhibition by a set of 5 putative transition-state mimics were determined. Excellent linear free energy relationships ( r = 0.97−0.99) were seen between binding of the inhibitors and transition-state affinities for aza-sugar inhibitors with sp 2 -hybridized “anomeric” centers, while lesser, but still significant, correlations were seen for sp 3 -hybridized inhibitors. Future design and elaboration of both classes of compounds as bespoke glycosidase inhibitors should be carried out with these findings clearly in mind.
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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 | 0.002 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 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".