ArticleJournal of the American Chemical Society2007
Structural analysis of charge discrimination in the binding of inhibitors to human carbonic anhydrases I and II.
Article in Journal of the American Chemical Society, 2007. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
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Who cites it
24 citing papers in PubMed, 68 citations in OpenAlex.
- Investigation onPharmaceuticals (Basel, Switzerland) · 2026Article
- Computational Approaches and Structure-Based Drug Design of CAIs.Sub-cellular biochemistry · 2026Review
- Review
- Exploration of Aromatic Hydrazides as Inhibitors of Human Carbonic Anhydrases.Archiv der Pharmazie · 2025Article
- Novel 3-Sulfonamide Dual-Tail Pyrrol-2-one Bridged Molecules as Potent Human Carbonic Anhydrase Isoform Inhibitors: Design, Synthesis, Molecular Modeling Investigation, and Anticancer Activity in MeWo, SK-BR-3, and MG-63 Cell Lines.Journal of medicinal chemistry · 2025Article
- Benzothiadiazinone-1,1-Dioxide Carbonic Anhydrase Inhibitors Suppress the Growth of Drug-ResistantInternational journal of molecular sciences · 2024Article
- Synthetic Approaches to Novel Human Carbonic Anhydrase Isoform Inhibitors Based on Pyrrol-2-one Moiety.Journal of medicinal chemistry · 2024Article
- Ebola virus VP35 interacts non-covalently with ubiquitin chains to promote viral replication.PLoS biology · 2024Article
- Inhibition Profiles of Some Novel Sulfonamide-Incorporated α-Aminophosphonates on Human Carbonic Anhydrases.ACS medicinal chemistry letters · 2023Article
- Ebola Virus VP35 Interacts Non-Covalently with Ubiquitin Chains to Promote Viral Replication Creating New Therapeutic Opportunities.bioRxiv : the preprint server for biology · 2023Article
- Discovery of Novel Hydroxyimine-Tethered Benzenesulfonamides as Potential Human Carbonic Anhydrase IX/XII Inhibitors.ACS medicinal chemistry letters · 2023Article
- Inhibition Studies on Human and Mycobacterial Carbonic Anhydrases withMolecules (Basel, Switzerland) · 2023Article
- Excimer-monomer fluorescence changes by supramolecular disassembly for protein sensing and quantification.Chemical communications (Cambridge, England) · 2021Article
- Sulfonamide Inhibitors of Human Carbonic Anhydrases Designed through a Three-Tails Approach: Improving Ligand/Isoform Matching and Selectivity of Action.Journal of medicinal chemistry · 2020Article
- Bioluminescent sensor proteins for point-of-care therapeutic drug monitoring.Nature chemical biology · 2014Article
- Effects of cryoprotectants on the structure and thermostability of the human carbonic anhydrase II-acetazolamide complex.Acta crystallographica. Section D, Biological crystallography · 2013Article
- Supramolecular displacement-mediated activation of a silent fluorescence probe for label-free ligand screening.Journal of the American Chemical Society · 2012Article
- Stabilization of anionic and neutral forms of a fluorophoric ligand at the active site of human carbonic anhydrase I.Biochimica et biophysica acta · 2010Article
- Atomic resolution studies of carbonic anhydrase II.Acta crystallographica. Section D, Biological crystallography · 2010Article
- High-resolution structure of human carbonic anhydrase II complexed with acetazolamide reveals insights into inhibitor drug design.Acta crystallographica. Section F, Structural biology and crystallization communications · 2009Article
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Authors and funding
8 authors at 2 institutions in 1 country.
Funding
Abstract
Despite the similarity in the active site pockets of carbonic anhydrase (CA) isozymes I and II, the binding affinities of benzenesulfonamide inhibitors are invariably higher with CA II as compared to CA I. To explore the structural basis of this molecular recognition phenomenon, we have designed and synthesized simple benzenesulfonamide inhibitors substituted at the para position with positively charged, negatively charged, and neutral functional groups, and we have determined the affinities and X-ray crystal structures of their enzyme complexes. The para-substituents are designed to bind in the midsection of the 15 A deep active site cleft, where interactions with enzyme residues and solvent molecules are possible. We find that a para-substituted positively charged amino group is more poorly tolerated in the active site of CA I compared with CA II. In contrast, a para-substituted negatively charged carboxylate substituent is tolerated equally well in the active sites of both CA isozymes. Notably, enzyme-inhibitor affinity increases upon neutralization of inhibitor charged groups by amidation or esterification. These results inform the design of short molecular linkers connecting the benzenesulfonamide group and a para-substituted tail group in "two-prong" CA inhibitors: an optimal linker segment will be electronically neutral, yet capable of engaging in at least some hydrogen bond interactions with protein residues and/or solvent. Microcalorimetric data reveal that inhibitor binding to CA I is enthalpically less favorable and entropically more favorable than inhibitor binding to CA II. This contrasting behavior may arise in part from differences in active site desolvation and the conformational entropy of inhibitor binding to each isozyme active site.
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