Structural and Thermodynamic Studies on Cation−Π Interactions in Lectin−Ligand Complexes: High-Affinity Galectin-3 Inhibitors through Fine-Tuning of an Arginine−Arene Interaction
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Bibliographic record
Abstract
The high-resolution X-ray crystal structures of the carbohydrate recognition domain of human galectin-3 were solved in complex with N-acetyllactosamine (LacNAc) and the high-affinity inhibitor, methyl 2-acetamido-2-deoxy-4-O-(3-deoxy-3-[4-methoxy-2,3,5,6-tetrafluorobenzamido]-beta-D-galactopyranose)-beta-D-glucopyranoside, to gain insight into the basis for the affinity-enhancing effect of the 4-methoxy-2,3,5,6-tetrafluorobenzamido moiety. The structures show that the side chain of Arg144 stacks against the aromatic moiety of the inhibitor, an interaction made possible by a reorientation of the side chain relative to that seen in the LacNAc complex. Based on these structures, synthesis of second generation LacNAc derivatives carrying aromatic amides at 3'-C, followed by screening with a novel fluorescence polarization assay, has led to the identification of inhibitors with further enhanced affinity for galectin-3 (K(d) > or = 320 nM). The thermodynamic parameters describing the binding of the galectin-3 C-terminal to selected inhibitors were determined by isothermal titration calorimetry and showed that the affinity enhancements were due to favorable enthalpic contributions. These enhancements could be rationalized by the combined effects of the inhibitor aromatic structure on a cation-Pi interaction and of direct interactions between the aromatic substituents and the protein. The results demonstrate that protein-ligand interactions can be significantly enhanced by the fine-tuning of arginine-arene interactions.
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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 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.000 | 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