Binding of sulfonium‐ion analogues of di‐<i>epi</i>‐swainsonine and 8‐<i>epi</i>‐lentiginosine to <i>Drosophila</i> Golgi α‐mannosidase II: The role of water in inhibitor binding
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
Retaining glycosidases operate by a two-step catalytic mechanism in which the transition states are characterized by buildup of a partial positive charge at the anomeric center. Sulfonium-ion analogues of the naturally occurring glycosidase inhibitors, swainsonine and 8-epi-lentiginosine, in which the bridgehead nitrogen atom is replaced by a sulfonium-ion, were synthesized in order to test the hypothesis that a sulfonium salt carrying a permanent positive charge would be an effective glycosidase inhibitor. Initial prediction based on computational docking indicated three plausible binding modes to Drosophila Golgi alpha-mannosidase II (dGMII), the most likely being close to that of swainsonine. Observation of the binding of di-epi-thioswainsonine and 8-epi-thiolentiginosine to dGMII from crystallographic data, however, revealed an orientation different from swainsonine in the active site. Screening these two compounds against dGMII shows that they are inhibitors with IC(50) values of 2.0 and 0.014 mM, respectively. This dramatic difference in affinity between the two compounds, which differ by only one hydroxyl group, is rationalized in terms of bound water molecules and the water molecule substructure in the active site, as identified by comparison of high resolution X-ray crystal structures of several dGMII-inhibitor complexes.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
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) | 0.000 | 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 | 0.000 |
| 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