9fn7 | pdb_00009fn7

Crystal structure of human carboanhydrase XII with 5,7,8-trifluoro-4-(3-propylhexyl)-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-sulfonamide 1,1-dioxide

spinqualitylabelsall models 9fn7, resolution 1.12Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 9fn7 is a 4 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.12Å Ligands: A1ID0, EDO, ZN Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease CAH12_HUMAN Defects in CA12 are the cause of hyperchlorhidrosis isolated (HCHLH) [MIM:143860. HCHLH is a disorder characterized by excessive sweating and increased sweat chloride levels. Affected individuals suffer from episodes of hyponatremic dehydration and report increased amounts of visible salt precipitates in sweat. Function CAH12_HUMAN Reversible hydration of carbon dioxide. Publication Abstract from PubMed High affinity and selectivity for intended targets is an important goal of small molecule design in drug discovery, yet balancing molecular flexibility and rigidity remains a challenge. While flexible compounds can increase target affinity, they often result in non-specific interactions and reduced selectivity. In contrast, rigid compounds may recognize their target more precisely and have lower off-target effects. In this study, we incorporated a 1,1-dioxido-1,4-thiazine ring into fluorinated benzenesulfonamide derivatives with bulky meta-substituents to enhance selectivity for human carbonic anhydrase IX (CAIX), an important cancer-associated target. Due to the structural similarities of CAIX with other carbonic anhydrase isozymes, selective inhibition remains a significant challenge. A series of 3,4-substituted trifluorobenzenesulfonamides containing oxidized thiazine rings were synthesized using a novel synthetic pathway. Although the potency against CAIX was modestly reduced compared to more flexible analogs, selectivity increased significantly, with lead compounds 7 d and 7 e exhibiting over 1000-fold selectivity for CAIX over most other isozymes. X-ray crystallography revealed the structural basis for this selectivity, confirming the advantageous positioning of rigidified compounds within some CA isozyme active sites. These findings highlight the potential of molecular rigidity in the design of highly selective inhibitors for therapeutic applications. Design of Rigid Compounds to Enhance Selectivity for Carbonic Anhydrase IX.,Vaskevicius A, Trumpickaite G, Parafjanovic E, Manakova E, Mickeviciute A, Gedgaudas M, Kojis T, Paketuryte-Latve V, Smirnov A, Baranauskiene L, Grazulis S, Zubriene A, Dudutiene V, Matulis D Chemistry. 2025 Mar 25;31(18):e202404409. doi: 10.1002/chem.202404409. Epub 2025 , Feb 17. PMID:39905940 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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