Inhibition of Mandelate Racemase by Boron-Based Inhibitors: Different Binding Modes for Benzoxaboroles Versus Boronic Acids
Bibliographic record
Abstract
Mandelate racemase (MR) catalyzes the Mg 2+ -dependent interconversion of ( R )- and ( S )-mandelate and has been employed as a model enzyme to demonstrate that an enzyme catalyzing the deprotonation of a carbon acid substrate may be inhibited by boronic acids. We report a detailed structure–activity-based study of the ability of various boronic acid derivatives to competitively inhibit MR. 2-Naphthylboronic acid ( K i = 0.32 ± 0.01 μM), furan-3-boronic acid ( K i = 10 ± 1 μM), and thiophene-3-boronic acid ( K i = 1.27 ± 0.06 μM) were potent inhibitors of MR, while 1-naphthylboronic acid ( K i = 28 ± 3 μM) and nitrogen-heterocycles ( e . g ., isoxazole, indole, 1 H -indazole, pyridine, and pyrimidine) bearing boronic acid groups were generally weaker inhibitors. A chlorine substituent on the pyridine ( i . e ., 2-chloro-pyridine-5-boronic or 2-chloro-pyridine-4-boronic acids) or pyrimidine ( i . e ., 2-chloro-pyrimidine-5-boronic acid) ring enhanced the binding affinity by 3- to 27-fold. Surprisingly, benzoxaboroles, including the antifungal agent tavaborole ( i . e ., 5-fluorobenzoxaborole, K i = 1.06 ± 0.09 μM), were also potent competitive inhibitors of MR. The pH-dependence of the inhibition by benzoxaborole suggested that the species with the tetrahedral, sp 3 -hybridized boron atom was the more potent inhibitor. Interestingly, 11 B NMR spectroscopy and X-ray crystallography revealed that aryl boronic acids and benzoxaboroles interact with MR via different binding modes. Unlike phenylboronic acid, which forms an N ε2 –B bond with His 297 at the active site, the 1.8-Å resolution structure of the MR-tavaborole adduct revealed the presence of an N ζ –B bond between the bound tavaborole and Lys 166 at the active site.
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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) | 0.000 | 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 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".