Thermodynamic properties of leukotriene A₄ hydrolase inhibitors

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.