Department of Biochemistry and Molecular Biology, College of Medicine, University of Florida, Gainesville, FL 32610, USA.
Acta Crystallogr F Struct Biol Commun. 2022 Nov 1;78(Pt 11):395-402. doi: 10.1107/S2053230X22009761. Epub 2022 Oct 14.
Carbonic anhydrases (CAs) are drug targets for a variety of diseases. While many clinically relevant CA inhibitors are sulfonamide-based, novel CA inhibitors are being developed that incorporate alternative zinc-binding groups, such as carboxylic acid moieties, to develop CA isoform-specific inhibitors. Here, the X-ray crystal structure of human CA II (hCA II) in complex with the carboxylic acid ibuprofen [2-(4-isobutylphenyl)propanoic acid, a common over-the-counter nonsteroidal anti-inflammatory drug] is reported to 1.54 Å resolution. The binding of ibuprofen is overlaid with the structures of other carboxylic acids in complex with hCA II to compare their inhibition mechanisms by direct or indirect (via a water) binding to the active-site zinc. Additionally, enzyme-inhibition assays using ibuprofen, nicotinic acid and ferulic acid were performed with hCA II to determine their IC values and were compared with those of other carboxylic acid binders. This study discusses the potential development of CA inhibitors utilizing the carboxylic acid moiety.
碳酸酐酶（CA）是多种疾病的药物靶点。虽然许多具有临床相关性的 CA 抑制剂基于磺胺类，但新型 CA 抑制剂正在被开发，这些抑制剂采用替代的锌结合基团，如羧酸部分，以开发针对 CA 同工型的特异性抑制剂。本文报道了人碳酸酐酶 II（hCA II）与羧酸布洛芬[2-（4-异丁基苯基）丙酸，一种常见的非甾体抗炎药]复合物的 X 射线晶体结构，分辨率为 1.54 Å。布洛芬的结合覆盖了与 hCA II 结合的其他羧酸的结构，以比较它们通过直接或间接（通过水）与活性位点锌结合的抑制机制。此外，还使用布洛芬、烟酸和阿魏酸进行了 hCA II 的酶抑制测定，以确定它们的 IC 值，并与其他羧酸结合物进行比较。本研究讨论了利用羧酸部分开发 CA 抑制剂的潜力。
