TY  - JOUR
AU  - Zakšauskas, Audrius
AU  - Čapkauskaitė, Edita
AU  - Jezepčikas, Linas
AU  - Linkuvienė, Vaida
AU  - Kišonaitė, Miglė
AU  - Smirnov, Alexey
AU  - Manakova, Elena
AU  - Grazulis, Saulius
AU  - Matulis, Daumantas
TI  - Design of two-tail compounds with rotationally fixed benzenesulfonamide ring as inhibitors of carbonic anhydrases
JO  - European journal of medicinal chemistry
VL  - 156
SN  - 0223-5234
CY  - Amsterdam [u.a.]
PB  - Elsevier
M1  - PUBDB-2018-05484
SP  - 61-78
PY  - 2018
N1  - © Elsevier Masson SAS. ; Final published version in progress; Post referee fulltext in progress; Embargo 12 months from publication
AB  - 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.
LB  - PUB:(DE-HGF)16
C6  - pmid:30006175
UR  - <Go to ISI:>//WOS:000443663200006
DO  - DOI:10.1016/j.ejmech.2018.06.059
UR  - https://bib-pubdb1.desy.de/record/417251
ER  -