Crystallographic studies of carbonic anhydrase isoforms and their complexes with inhibitors /

Crystallographic studies of carbonic anhydrase isoforms and their complexes with inhibitors The goal of this study was 1) to solve the crystal structures of the complexes of several CA isoforms with a series of sulfonamide inhibitors using X-ray crystallography technique, 2) to analyze the interactions between the ligands and the CA proteins, determine the mechanisms of binding selectivity, affinity, and 3) search for the correlations between the structure and the binding thermodynamic parameters. In this work, we have published 61 crystal structures of newly synthesized sulfonamide-based CA inhibitors with 5 CA isoforms (CA I, CA II, CA IV, CA XII, and CA XIII) and also 2 mutant CA II proteins. The binding of a series of newly synthesized sulfonamides in the active sites of 5 CA isoforms was studied in detail. The mechanism of molecular recognition that increases the binding affinity to the target CA was proposed. The recognition mechanism of CA IX selective binder was studied in detail explaining the crystallographic data. The meta-cyclooctyl ring of the lead compound VD11-4-2 interacts with the hydrophobic pocket available only in the CA IX isoform and not in CA I, CA II, and CA XIII. We have described the tendencies of the changes in the binding thermodynamics between structurally similar compounds. This helps in the design of new compounds with the desired properties.

Grantor dc:publisher

Institutional Repository of Vilnius University

Year dc:date

2018

Author dc:creator

• Smirnov, Alexey,

Contributors dc:contributor

• Matulis, Daumantas

• X-ray crystallography ; Structure-thermodynamics relationships ; Intrinsic thermodynamics of binding ; Carbonic anhydrase inhibitors

Statement dc:rights

• info:eu-repo/semantics/openAccess

Language dc:language

eng

Repository record dc:identifier

https://repository.vu.lt/VU:ELABAETD31672036&prefLang=en_US

OAI identifier oai:identifier

oai:vu.lt:elaba:31672036