Modeling predicts facile release of nitrite but not nitric oxide from the thionitrate CH3SNO2 with relevance to nitroglycerin bioactivation
Bibliographic record
Abstract
Nitroglycerin is a potent vasodilator in clinical use since the late 1800s. It functions as a prodrug that is bioactivated by formation of an enzyme-based thionitrate, E–Cys–NO2. This intermediate reportedly decomposes to release NO and NO2− but their relative yields remain controversial. Hence, we determined barriers for NO and NO2− production from the model thionitrate, CH3SNO2, using comprehensive high-level quantum chemistry calculations [CCSD(T)//MP2/aug-cc-pVTZ]. We find that the sulfenyl nitrite, CH3SONO, readily releases NO on (S)O–N bond homolysis but CH3SONO formation from CH3SNO2 either by S–NO2 bond homolysis or concerted rearrangement faces prohibitively high barriers (ΔHcalc/ΔH‡calc > 42 kcal/mol). Dramatically lower barriers (ΔH‡calc ~ 17–21 kcal/mol) control NO2− release from CH3SNO2 by gas-phase hydrolysis or nucleophilic attack by OH− or CH3S− on the sulfur atom within the C–S–NO2 molecular plane. Moreover, attack by either anion along the S–NO2 bond results in barrierless NO2− release (ΔH‡calc ~ 0 kcal/mol) since a σ-hole (i.e., area of positive electrostatic potential) extends from this bond. Consistent with our high-level calculations, ALDH2 and GAPDH, enzymes implicated in nitroglycerin bioactivation via an E–Cys–NO2 intermediate, catalyze mainly or exclusively NO2− release from the prodrug.
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.
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 | 0.001 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.001 | 0.000 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.003 | 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".