Balandis Benas, Šimkūnas Tomas, Paketurytė-Latvė Vaida, Michailovienė Vilma, Mickevičiūtė Aurelija, Manakova Elena, Gražulis Saulius, Belyakov Sergey, Kairys Visvaldas, Mickevičius Vytautas, Zubrienė Asta, Matulis Daumantas
Department of Organic Chemistry, Kaunas University of Technology, Radvilėnų pl. 19, LT-50254 Kaunas, Lithuania.
Department of Biothermodynamics and Drug Design, Institute of Biotechnology, Life Sciences Center, Vilnius University, Saulėtekio 7, LT-10257 Vilnius, Lithuania.
Pharmaceuticals (Basel). 2022 Apr 13;15(4):477. doi: 10.3390/ph15040477.
A series of novel benzenesulfonamide derivatives were synthesized bearing - β,γ-amino acid or - β-amino acid and thiazole moieties and their binding to the human carbonic anhydrase (CA) isozymes determined. These enzymes are involved in various illnesses, such as glaucoma, altitude sickness, epilepsy, obesity, and even cancer. There are numerous compounds that are inhibitors of CA and used as pharmaceuticals. However, most of them bind to most CA isozymes with little selectivity. The design of high affinity and selectivity towards one CA isozyme remains a significant challenge. The beta and gamma amino acid-substituted compound affinities were determined by the fluorescent thermal shift assay and isothermal titration calorimetry for all 12 catalytically active human carbonic anhydrase isozymes, showing the full affinity and selectivity profile. The structures of several compounds were determined by X-ray crystallography, and the binding mode in the active site of CA enzyme was shown.
合成了一系列带有-β,γ-氨基酸或-β-氨基酸以及噻唑部分的新型苯磺酰胺衍生物，并测定了它们与人碳酸酐酶（CA）同工酶的结合情况。这些酶参与多种疾病，如青光眼、高原病、癫痫、肥胖症甚至癌症。有许多化合物是CA的抑制剂并用作药物。然而，它们中的大多数对大多数CA同工酶的结合选择性很小。设计对一种CA同工酶具有高亲和力和选择性仍然是一项重大挑战。通过荧光热位移分析和等温滴定量热法测定了β和γ氨基酸取代化合物对所有12种具有催化活性的人碳酸酐酶同工酶的亲和力，显示了完整的亲和力和选择性概况。通过X射线晶体学确定了几种化合物的结构，并展示了它们在CA酶活性位点的结合模式。
