6G7A

Crystal structure of human carbonic anhydrase isozyme XII 2-(benzylamino)-4-chloro-N-(2-hydroxyethyl)-5-sulfamoyl-benzamide

Summary for 6G7A

• Entry DOI: 10.2210/pdb6g7a/pdb
• Related: 6G5L 6G5U 6G6T
• Descriptor: Carbonic anhydrase 12, ZINC ION, 1,2-ETHANEDIOL, ... (5 entities in total)
• Functional Keywords: drug design, carbonic anhydrase, benzenesulfonamide, metal-binding, lyase-lyase inhibitor comple, lyase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 4
• Total formula weight: 122211.12

Authors

Smirnov, A.,Manakova, E.,Grazulis, S. (deposition date: 2018-04-05, release date: 2019-03-13, Last modification date: 2024-11-06)

Primary citation

Zaksauskas, A.,Capkauskaite, E.,Jezepcikas, L.,Linkuviene, V.,Kisonaite, M.,Smirnov, A.,Manakova, E.,Grazulis, S.,Matulis, D.
Design of two-tail compounds with rotationally fixed benzenesulfonamide ring as inhibitors of carbonic anhydrases.
Eur J Med Chem, 156:61-78, 2018

PubMed Abstract: Rational design of compounds that would bind specific pockets of the target proteins is a difficult task in drug design. The 12 isoforms of catalytically active human carbonic anhydrases (CAs) have highly similar active sites that make it difficult to design inhibitors selective for one or several CA isoforms. A series of CA inhibitors based on 2-chloro/bromo-benzenesulfonamide that is largely fixed in the CA active site together with one or two tails yielded compounds that were synthesized and evaluated as inhibitors of CA isoforms. Introduction of a second tail had significant influence on the binding affinity and two-tailed compounds in most cases provided high affinity and selectivity for CA IX and CA XIV. The contacts between several compounds and CA amino acids were determined by X-ray crystallography. Together with the intrinsic enthalpy and entropy of binding they provided the structure-thermodynamics correlations for this series of compounds with the insight how to rationally build compounds with desired CA isoform as a target.

PubMed: 30006175
DOI: 10.1016/j.ejmech.2018.06.059

Experimental method

X-RAY DIFFRACTION (1.42 Å)