The Mechanism of Action of Carbonic Anhydrase

1990 ◽  
pp. 181-197 ◽  
Author(s):  
L. Banci ◽  
I. Bertini ◽  
C. Luchinat ◽  
J. M. Moratal
Keyword(s):  
Carbonic Anhydrase ◽  
Mechanism Of Action

On the mechanism of action of carbonic anhydrase

1973 ◽  
Vol 2 (4) ◽  
pp. 337-344 ◽  
Author(s):  
R.H. Prince ◽  
P.R. Woolley
Keyword(s):  
Carbonic Anhydrase ◽  
Mechanism Of Action

scholarly journals Again about carbonic anhydrase inhibitors: modern aspects of the use of ICA in ophthalmology

2021 ◽  
Vol 9 (2) ◽  
pp. 64-71
Author(s):  
P.A. Bezdetko
Keyword(s):  
Antioxidant Activity ◽  
Intraocular Pressure ◽  
Optic Nerve ◽  
Carbonic Anhydrase ◽  
Macular Edema ◽  
Mechanism Of Action ◽  
Corneal Endothelium ◽  
Complex Treatment ◽  
Efficacy And Safety ◽  
Carbonic Anhydrase Inhibitors

For more than 70 years, the inhibitors of carbonic anhydrase (ICA) have been used in the treatment of glaucoma. Since 1995, topical forms of ICA have appeared among antiglaucoma drugs — dorzolamide, and since 1999 — brinzolamide. The hypotensive efficacy and safety of topical ICA gave rise to the widespread use of these drugs in the treatment of various forms of glaucoma. The peculiarities of the mechanism of action made it possible to create on their basis effective fixed combinations, which allow reducing the intraocular pressure by up to 40 % in patients with glaucoma. The attractiveness of the drug has expanded due to the effect of ICA on various tissues of the organ of vision. Thus, ICAs effectively improve the hemodynamics of the eye and optic nerve. The antioxidant activity of the drug makes it possible to expand the indications for its use in patients with vascular patho-logy of the retina and optic nerve. The biomechanical characte-ristics of the drug allowed its effective and safe use in the complex treatment of macular edema of various etiologies. The adjuvant use of topical ICAs expands the possibilities of anti-VEGF therapy in the treatment of macular edema of various etiologies. Features of the action of ICA on the endothelial pump function of the cornea made it possible to formulate the rules for the use of topical ICA in patients with an insufficient function of the corneal endothelium.

scholarly journals A new approach to antiglaucoma drugs: carbonic anhydrase inhibitors with or without NO donating moieties. Mechanism of action and preliminary pharmacology

2011 ◽  
Vol 27 (1) ◽  
pp. 138-147 ◽  
Author(s):  
Francesca Fabrizi ◽  
Francesco Mincione ◽  
Teresa Somma ◽  
Gabriele Scozzafava ◽  
Fernando Galassi ◽  
...  
Keyword(s):  
Carbonic Anhydrase ◽  
Mechanism Of Action ◽  
Carbonic Anhydrase Inhibitors ◽  
New Approach

scholarly journals Inhibition Profiling of Human Carbonic Anhydrase II by High-Throughput Screening of Structurally Diverse, Biologically Active Compounds

2006 ◽  
Vol 11 (7) ◽  
pp. 782-791 ◽  
Author(s):  
Rema Iyer ◽  
Albert A. Barrese ◽  
Shilpa Parakh ◽  
Christian N. Parker ◽  
Brian C. Tripp
Keyword(s):  
Carbonic Anhydrase ◽  
Small Molecules ◽  
Tannic Acid ◽  
High Throughput ◽  
Mechanism Of Action ◽  
High Throughput Screening ◽  
Biologically Active ◽  
Carbonic Anhydrase Ii ◽  
Hit Rate ◽  
Human Carbonic Anhydrase

Human carbonic anhydrase II (CA II), a zinc metalloenzyme, was screened against 960 structurally diverse, biologically active small molecules. The assay monitored CA II esterase activity against the substrate 4-nitrophenyl acetate in a format allowing high-throughput screening. The assay proved to be robust and reproducible with a hit rate of ∼2%. Potential hits were further characterized by determining their IC50 and Kd values and tested for nonspecific, promiscuous inhibition. Three known sulfonamide CA inhibitors were identified: acetazolamide, methazolamide, and celecoxib. Other hits were also found, including diuretics and antibiotics not previously identified as CA inhibitors, for example, furosemide and halazone. These results confirm that many sulfonamide drugs have CA inhibitory properties but also that not all sulfonamides are CA inhibitors. Thus many, but not all, sulfonamide drugs appear to interact with CA II and may target other CA isozymes. The screen also yielded several novel classes of nonsulfonamide inhibitors, including merbromin, thioxolone, and tannic acid. Although these compounds may function by some nonspecific mechanism (merbromin and tannic acid), at least 1 (thioxolone) appears to represent a genuine CA inhibitor. Thus, this study yielded a number of potentially new classes of CA inhibitors and preliminary experiments to characterize their mechanism of action.

scholarly journals Mechanism of Action of Non-Synonymous Single Nucleotide Variations Associated with α-Carbonic Anhydrase II Deficiency

Molecules ◽  
2019 ◽  
Vol 24 (21) ◽  
pp. 3987 ◽  
Author(s):  
Taremekedzwa Allan Sanyanga ◽  
Bilal Nizami ◽  
Özlem Tastan Bishop
Keyword(s):  
Carbonic Anhydrase ◽  
Mechanism Of Action ◽  
Active Site ◽  
The Body ◽  
Carbonic Anhydrase Ii ◽  
Motif Analysis ◽  
Acid Base Balance ◽  
Compensatory Mechanisms ◽  
Single Nucleotide ◽  
Single Nucleotide Variations

Human carbonic anhydrase II (CA-II) is a Zinc (Zn 2 + ) metalloenzyme responsible for maintenance of acid-base balance within the body through the reversible hydration of CO 2 to produce protons (H + ) and bicarbonate (BCT). Due to its importance, alterations to the amino acid sequence of the protein as a result of single nucleotide variations (nsSNVs) have detrimental effects on homeostasis. Six pathogenic CA-II nsSNVs, K18E, K18Q, H107Y, P236H, P236R and N252D were identified, and variant protein models calculated using homology modeling. The effect of each nsSNV was analyzed using motif analysis, molecular dynamics (MD) simulations, principal component (PCA) and dynamic residue network (DRN) analysis. Motif analysis identified 11 functionally important motifs in CA-II. RMSD data indicated subtle SNV effects, while PCA analysis revealed that the presence of BCT results in greater conformational sampling and free energy in proteins. DRN analysis showed variant allosteric effects, and the average betweenness centrality (BC) calculations identified Glu117 as the most important residue for communication in CA-II. The presence of BCT was associated with a reduction to Glu117 usage in all variants, suggesting implications for Zn 2 + dissociation from the CA-II active site. In addition, reductions to Glu117 usage are associated with increases in the usage of the primary and secondary Zn 2 + ligands; His94, His96, His119 and Asn243 highlighting potential compensatory mechanisms to maintain Zn 2 + within the active site. Compared to traditional MD simulation investigation, DRN analysis provided greater insights into SNV mechanism of action, indicating its importance for the study of missense mutation effects in proteins and, in broader terms, precision medicine related research.

scholarly journals Novel 8-Substituted Coumarins That Selectively Inhibit Human Carbonic Anhydrase IX and XII

2019 ◽  
Vol 20 (5) ◽  
pp. 1208 ◽  
Author(s):  
Kerem Buran ◽  
Silvia Bua ◽  
Giulio Poli ◽  
F. Önen Bayram ◽  
Tiziano Tuccinardi ◽  
...  
Keyword(s):  
Molecular Modeling ◽  
Carbonic Anhydrase ◽  
Mechanism Of Action ◽  
Inhibitory Activity ◽  
Carbonic Anhydrase Ix ◽  
Specific Mechanism ◽  
Single Digit ◽  
Molecular Modeling Studies ◽  
Human Carbonic Anhydrase ◽  
Substituted Coumarins

A novel series of 8-substituted coumarin-based compounds, characterized by the presence of alkylpiperazine and arylpiperazine chains, were synthesized and tested for their inhibitory activity against four human carbonic anhydrase (hCA) isoforms. All compounds displayed nanomolar potency against the cancer-related hCA IX and hCA XII; moreover, they were shown to be devoid of any inhibitory activity toward the cytosolic hCA I and hCA II up to 10 µM concentration in the assay system. Therefore, the synthesized coumarin ligands demonstrated to be potent and selective hCA IX/XII inhibitors, and were shown to be as potent as the reference inhibitor acetazolamide against hCA XII, with single-digit nanomolar Ki values. Molecular modeling studies provided a rationale for explaining the selectivity profile of these non-classic hCA inhibitors and their interactions with the enzymes, according to their specific mechanism of action, thus paving the way for future structure-based lead optimization studies.

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