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Bioorg Med Chem. 2016 Nov 1;24(21):5243-5248. doi: 10.1016/j.bmc.2016.08.047. Epub 2016 Aug 26.

Thermodynamic properties of leukotriene A4 hydrolase inhibitors.

Author information

1
Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, Max-von-Laue-Street 9, 60438 Frankfurt, Germany. Electronic address: Wittmann@pharmchem.uni-frankfurt.de.
2
Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, Max-von-Laue-Street 9, 60438 Frankfurt, Germany. Electronic address: Kalinowsky@pharmchem.uni-frankfurt.de.
3
Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, Max-von-Laue-Street 9, 60438 Frankfurt, Germany. Electronic address: J.Kramer@pharmchem.uni-frankfurt.de.
4
Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, Max-von-Laue-Street 9, 60438 Frankfurt, Germany. Electronic address: bloecher@pharmchem.uni-frankfurt.de.
5
Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, Max-von-Laue-Street 9, 60438 Frankfurt, Germany. Electronic address: Knapp@pharmchem.uni-frankfurt.de.
6
Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, Max-von-Laue-Street 9, 60438 Frankfurt, Germany. Electronic address: steinhilber@em.uni-frankfurt.de.
7
Institute of Biochemistry, Goethe University Frankfurt, Max-von-Laue Street 9, 60438 Frankfurt, Germany. Electronic address: pogoryelov@em.uni-frankfurt.de.
8
Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, Max-von-Laue-Street 9, 60438 Frankfurt, Germany. Electronic address: proschak@pharmchem.uni-frankfurt.de.
9
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.

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.

KEYWORDS:

Apo structure; LTA(4)H; Ligand binding; Water mapping

PMID:
27651294
DOI:
10.1016/j.bmc.2016.08.047
[Indexed for MEDLINE]

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