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.

中文翻译：

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抑制剂与人碳酸酐酶的多种结合模式：亚型特异性活性调节剂设计的最新进展


人碳酸酐酶 （hCA） 是广泛使用的锌酶，可催化 CO₂ 水合为碳酸氢盐和质子。目前，已鉴定出 15 种亚型，其中只有 12 种具有催化活性。鉴于 hCA 参与许多生理和病理过程，hCA 是公认的开发具有生物医学应用的抑制剂的治疗靶标。然而，尽管进行了大量开发工作，但目前可用的 hCA 抑制剂中很少有对特定亚型表现出选择性。X 射线晶体学是酶抑制剂合理药物设计的非常有用的工具。2012 年，我们在《化学评论》上发表了一篇关于 hCA 家族的高引用综述 （Alterio， V. et al. Chem Rev.2012， 112， 4421−4468），分析了 hCA/抑制剂复合物的大约 300 种晶体结构，并描述了迄今为止存在的不同 CA 抑制机制。然而，在 2012-2023 年期间，PDB 中沉积了近 700 种新的 hCA/抑制剂复合物结构，并发现了大量新的抑制剂类别。基于这些考虑，本综述的目的是对 2012-2023 年期间 hCA/抑制剂相互作用的结构方面进行全面更新，并概括如何将这些信息用于此类抑制剂的更具选择性版本的合理设计。