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Conformational Changes in Alkyl Chains Determine the Thermodynamic and Kinetic Binding Profiles of Carbonic Anhydrase Inhibitors
journal contribution
posted on 2020-02-19, 19:40 authored by Steffen Glöckner, Khang Ngo, Christoph P. Sager, Tobias Hüfner-Wulsdorf, Andreas Heine, Gerhard KlebeThermodynamics and
kinetics of protein–ligand binding are
both important aspects for the design of novel drug molecules. Presently,
thermodynamic data are collected with isothermal titration calorimetry,
while kinetic data are mostly derived from surface plasmon resonance.
The new method of kinITC provides both thermodynamic and kinetic data
from calorimetric titration measurements. The present study demonstrates
the convenient collection of calorimetric data suitable for both thermodynamic
and kinetic analysis for two series of congeneric ligands of human
carbonic anhydrase II and correlates these findings with structural
data obtained by macromolecular crystallography to shed light on the
importance of shape complementarity for thermodynamics and kinetics
governing a protein–ligand binding event. The study shows how
minute chemical alterations change preferred ligand conformation and
can be used to manipulate thermodynamic and kinetic signatures of
binding. They give rise to the observation that analogous n-alkyl and n-alkyloxy derivatives of identical
chain length swap their binding kinetic properties at unchanged binding
affinity.
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carbonic anhydrase IIsurface plasmon resonancecongeneric ligandstitration calorimetryproteinkineticConformational Changesshape complementarityCarbonic Anhydrase Inhibitors ThermodynamicsKinetic Binding Profileschain length swaptitration measurementsbinding affinitydataminute chemical alterations changenovel drug moleculesAlkyl Chainsalkyloxy derivativesligand conformation
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