The structural basis for the selectivity of sulfonamide-based inhibitors of carbonic anhydrase isoforms IX and XII: A comprehensive review of the crystallographic data
Bibliographic record
Abstract
Hypoxia, a shortage of oxygen arising from a cancer tumour’s inability to sufficiently vascularize in response to the metabolic demands, reliably alters the regulation of an array of genes in solid cancers, including the significant upregulation of carbonic anhydrases (CAs). CAs are a ubiquitously expressed family of zinc-dependent metalloenzymes that maintain pH homeostasis by catalyzing the interconversion of carbon dioxide and water to bicarbonate and protons. Most of the 15 human α-CA isozymes are overexpressed in cancers, but CA IX and CA XII in particular have expression profiles that make them both promising diagnostic and prognostic candidates, and putative anticancer drug targets as their inhibition in healthy tissue is likely tolerated; however, it is a daunting task to design inhibitors selective for these two cancer-associated CAs due to the high structural similarity among all the human CAs, and the dangers inherent in pan-CA inhibition. Fortunately, this is becoming feasible with the accumulation of structural information arising from crystallography and Cryo-EM experiments—unfortunately, this data must be curated by the researcher as it is not analyzed in a single place. This review addresses this problem by discussing all available crystal data of ligand-cocrystallized CA IX and CA XII, and then juxtaposes these structures with those of CA II (the ubiquitous CA) complexes to better understand what features lend themselves to ligand specificity. The resulting comparative analysis of the 64 X-ray structures of sulfonamides cocrystallized with CA II, CA IX, and CA XII can help focus attention on promising avenues of future experimentation.
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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 | 0.001 | 0.001 |
| Meta-epidemiology (narrow) | 0.001 | 0.001 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.000 | 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) | 0.001 | 0.001 |
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".