Design of two-tail compounds with rotationally fixed benzenesulfonamide ring as inhibitors of carbonic anhydrases
- Resource Type
- Authors
- M. Kisonaite; Vaida Linkuviene; Edita Capkauskaite; Elena Manakova; Daumantas Matulis; Saulius Grazulis; Audrius Zakšauskas; L. Jezepcikas; Alexey Smirnov
- Source
- European Journal of Medicinal Chemistry. 156:61-78
- Subject
- 0301 basic medicine
Gene isoform
Halogenation
Stereochemistry
Crystallography, X-Ray
01 natural sciences
Structure-Activity Relationship
03 medical and health sciences
Antigens, Neoplasm
Catalytic Domain
Carbonic anhydrase
Drug Discovery
Humans
Protein Isoforms
Carbonic Anhydrase IX
Carbonic Anhydrase Inhibitors
Carbonic Anhydrases
Pharmacology
chemistry.chemical_classification
Sulfonamides
Binding Sites
biology
Chemistry
Organic Chemistry
Rational design
Active site
General Medicine
Lyase
0104 chemical sciences
Amino acid
Molecular Docking Simulation
010404 medicinal & biomolecular chemistry
030104 developmental biology
Drug Design
biology.protein
Thermodynamics
Selectivity
Protein Binding
Entropy (order and disorder)
- Language
- ISSN
- 0223-5234
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.