Thermodynamic properties of leukotriene A4 hydrolase inhibitors. Issue 21 (1st November 2016)

• Record Type: Journal Article
• Authors: Wittmann, Sandra K.; Kalinowsky, Lena; Kramer, Jan S.; Bloecher, René; Knapp, Stefan; Steinhilber, Dieter; Pogoryelov, Denys; Proschak, Ewgenij; Heering, Jan
• Is Part Of: Bioorganic & medicinal chemistry. Volume 24:Issue 21(2016)
• Page Start: 5243
• Page End: 5248
• Publication Date: 2016-11-01
• Subjects: LTA4H leukotriene A4 hydrolase -- LTA4 leukotriene A4 -- LTB4 leukotriene B4 -- kDa kilo Dalton -- PGP prolin–glycin–prolin -- TSA thermal shift assay -- TM melting point -- ITC isothermal titration calorimetry -- DSF different scanning fluorimetry -- Ki inhibitory constant -- Kd dissoziation constant; LTA4H -- Apo structure -- Water mapping -- Ligand binding; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2016.08.047
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Abstract: The leukotriene A4 hydrolase (LTA4 H) 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 LTA4 H 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 LTA4 H is used to interpret the measured thermodynamic data and provided insights for design of novel LTA4 H inhibitors.