title: Thermodynamic properties of leukotriene A4hydrolase inhibitors.
abstract: The leukotriene A4hydrolase (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 A4to 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.
authors.affiliation: Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, Max-von-Laue-Street 9, 60438 Frankfurt, Germany. Electronic address: Wittmann@pharmchem.uni-frankfurt.de.
authors.forename: Sandra K
authors.initials: SK
authors.lastname: Wittmann
authors.affiliation: Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, Max-von-Laue-Street 9, 60438 Frankfurt, Germany. Electronic address: Kalinowsky@pharmchem.uni-frankfurt.de.
authors.forename: Lena
authors.initials: L
authors.lastname: Kalinowsky
authors.affiliation: Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, Max-von-Laue-Street 9, 60438 Frankfurt, Germany. Electronic address: J.Kramer@pharmchem.uni-frankfurt.de.
authors.forename: Jan S
authors.initials: JS
authors.lastname: Kramer
authors.affiliation: Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, Max-von-Laue-Street 9, 60438 Frankfurt, Germany. Electronic address: bloecher@pharmchem.uni-frankfurt.de.
authors.forename: René
authors.initials: R
authors.lastname: Bloecher
authors.affiliation: Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, Max-von-Laue-Street 9, 60438 Frankfurt, Germany. Electronic address: Knapp@pharmchem.uni-frankfurt.de.
authors.forename: Stefan
authors.initials: S
authors.lastname: Knapp
authors.affiliation: Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, Max-von-Laue-Street 9, 60438 Frankfurt, Germany. Electronic address: steinhilber@em.uni-frankfurt.de.
authors.forename: Dieter
authors.initials: D
authors.lastname: Steinhilber
authors.affiliation: Institute of Biochemistry, Goethe University Frankfurt, Max-von-Laue Street 9, 60438 Frankfurt, Germany. Electronic address: pogoryelov@em.uni-frankfurt.de.
authors.forename: Denys
authors.initials: D
authors.lastname: Pogoryelov
authors.affiliation: Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, Max-von-Laue-Street 9, 60438 Frankfurt, Germany. Electronic address: proschak@pharmchem.uni-frankfurt.de.
authors.forename: Ewgenij
authors.initials: E
authors.lastname: Proschak
authors.affiliation: Fraunhofer Institute for Molecular Biology and Applied Ecology IME, Project Group Translational Medicine and Pharmacology TMP, Theodor-Stern-Kai 7, D-60596 Frankfurt am Main, Germany. Electronic address: Jan.Heering@ime.fraunhofer.de.
authors.forename: Jan
authors.initials: J
authors.lastname: Heering
mesh_terms: D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D013816:Thermodynamics
chemical_list: D004791:Enzyme Inhibitors; D004851:Epoxide Hydrolases; C043134:leukotriene A4 hydrolase
keywords: Apo structure; LTA(4)H; Ligand binding; Water mapping