5E2N

Crystal structure of human carbonic anhydrase isozyme XIII with 3-(cyclooctylamino)-2,5,6-trifluoro-4-[(2-hydroxyethyl)sulfonyl]benzenesulfonamide

Summary for 5E2N

• Entry DOI: 10.2210/pdb5e2n/pdb
• Related: 5DOG 5DOH 5DRS 5E2M
• Descriptor: Carbonic anhydrase 13, ZINC ION, DI(HYDROXYETHYL)ETHER, ... (7 entities in total)
• Functional Keywords: drug design, carbonic anhydrase, benzenesulfonamide, metal-binding, lyase-lyase inhibitor complex, lyase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 60979.15

Authors

Manakova, E.,Smirnov, A.,Grazulis, S. (deposition date: 2015-10-01, release date: 2016-10-05, Last modification date: 2024-01-10)

Primary citation

Zubriene, A.,Smirnov, A.,Dudutiene, V.,Timm, D.D.,Matuliene, J.,Michailoviene, V.,Zaksauskas, A.,Manakova, E.,Grazulis, S.,Matulis, D.
Intrinsic Thermodynamics and Structures of 2,4- and 3,4-Substituted Fluorinated Benzenesulfonamides Binding to Carbonic Anhydrases.
ChemMedChem, 12:161-176, 2017

PubMed Abstract: The goal of rational drug design is to understand structure-thermodynamics correlations in order to predict the chemical structure of a drug that would exhibit excellent affinity and selectivity for a target protein. In this study we explored the contribution of added functionalities of benzenesulfonamide inhibitors to the intrinsic binding affinity, enthalpy, and entropy for recombinant human carbonic anhydrases (CA) CA I, CA II, CA VII, CA IX, CA XII, and CA XIII. The binding enthalpies of compounds possessing similar chemical structures and affinities were found to be very different, spanning a range from -90 to +10 kJ mol , and are compensated by a similar opposing entropy contribution. The intrinsic parameters of binding were determined by subtracting the linked protonation reactions. The sulfonamide group pK values of the compounds were measured spectrophotometrically, and the protonation enthalpies were measured by isothermal titration calorimetry (ITC). Herein we describe the development of meta- or ortho-substituted fluorinated benzenesulfonamides toward the highly potent compound 10 h, which exhibits an observed dissociation constant value of 43 pm and an intrinsic dissociation constant value of 1.1 pm toward CA IX, an anticancer target that is highly overexpressed in various tumors. Fluorescence thermal shift assays, ITC, and X-ray crystallography were all applied in this work.

PubMed: 28001003
DOI: 10.1002/cmdc.201600509

Experimental method

X-RAY DIFFRACTION (1.53 Å)