Developing high affinity oligosaccharide inhibitors: conformational pre-organization paired with functional group modification
Bibliographic record
Abstract
Intramolecular tethering combined with functional group modification has been investigated as an approach to design high affinity oligosaccharide ligands. The preceding paper reported successful tethering to constrain a trisaccharide in the conformation of its bound state with an antibody and thereby achieved a 15-fold increase in association constant. Here we report the synthesis of two beta-alanyl tethered derivatives that employ monochlorination and monodeoxygenation strategies to create inhibitors that should enhance the binding affinity of the target molecules by an additional 10-25-fold, provided that free energy changes are additive when tethering is paired with functional group changes. The binding parameters of the new ligands were measured by isothermal titration calorimetry and the results rationalized with molecular dynamics calculations and a simple docking analysis. The data indicate that while the alanine tether is a reasonable method to constrain trisaccharide , free energy gains obtained by pairing it with functional group modification are not additive and in one case counter-productive.
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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) | 0.000 | 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 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 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".