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 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) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 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) | 0.001 | 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".