Title
Thermodynamic properties of leukotriene A4 hydrolase inhibitors
Author
Sandra K. Wittmann, Lena Kalinowsky, Jan S. Kramer, René Bloecher, Stefan Knapp, Dieter Steinhilber, Denys Pogoryelov, Ewgenij Proschak, Jan Heering
Year
2016
Journal
Bioorganic & Medicinal Chemistry
Abstract
The leukotriene A4 hydrolase (LTA4H) is a bifunctional enzyme, containing a peptidase and a hydrolase activity both activities having opposing functions regulating inflammatory response. The hydrolase activity is responsible for the conversion of leukotriene A4 to pro-inflammatory leukotriene B4, and hence, selective inhibitors of the hydrolase activity are of high pharmacological interest. Here we present the thermodynamic characterization of structurally distinct inhibitors of the LTA4H that occupy different regions of the binding site using different biophysical methods. An in silico method for the determination of stabilized water molecules in the binding site of the apo structure of LTA4H is used to interpret the measured thermodynamic data and provided insights for design of novel LTA4H inhibitors.
Instrument
J-810
Keywords
Circular dichroism, Secondary structure, Ligand binding, Thermal stability, Thermodynamics, Biochemistry