Multiple Binding Modes of Inhibitors to Human Carbonic Anhydrases: An Update on the Design of Isoform-Specific Modulators of Activity

IF 51.4 1区 化学 Q1 CHEMISTRY, MULTIDISCIPLINARY Chemical Reviews Pub Date : 2024-12-19 DOI:10.1021/acs.chemrev.4c00278
Katia D’Ambrosio, Anna Di Fiore, Vincenzo Alterio, Emma Langella, Simona Maria Monti, Claudiu T. Supuran, Giuseppina De Simone
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Abstract

Human carbonic anhydrases (hCAs) are widespread zinc enzymes that catalyze the hydration of CO2 to bicarbonate and a proton. Currently, 15 isoforms have been identified, of which only 12 are catalytically active. Given their involvement in numerous physiological and pathological processes, hCAs are recognized therapeutic targets for the development of inhibitors with biomedical applications. However, despite massive development efforts, very few of the presently available hCA inhibitors show selectivity for a specific isoform. X-ray crystallography is a very useful tool for the rational drug design of enzyme inhibitors. In 2012 we published in Chemical Reviews a highly cited review on hCA family (Alterio, V. et al. Chem Rev. 2012, 112, 4421−4468), analyzing about 300 crystallographic structures of hCA/inhibitor complexes and describing the different CA inhibition mechanisms existing up to that date. However, in the period 2012–2023, almost 700 new hCA/inhibitor complex structures have been deposited in the PDB and a large number of new inhibitor classes have been discovered. Based on these considerations, the aim of this Review is to give a comprehensive update of the structural aspects of hCA/inhibitor interactions covering the period 2012–2023 and to recapitulate how this information can be used for the rational design of more selective versions of such inhibitors.

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Chemical Reviews
Chemical Reviews 化学-化学综合
CiteScore
106.00
自引率
1.10%
发文量
278
审稿时长
4.3 months
期刊介绍: Chemical Reviews is a highly regarded and highest-ranked journal covering the general topic of chemistry. Its mission is to provide comprehensive, authoritative, critical, and readable reviews of important recent research in organic, inorganic, physical, analytical, theoretical, and biological chemistry. Since 1985, Chemical Reviews has also published periodic thematic issues that focus on a single theme or direction of emerging research.
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