Thermodynamic properties of leukotriene A₄ hydrolase inhibitors

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• 作者：Sandra K. Wittmann^a ; ^{Wittmann@pharmchem.uni-frankfurt.de" class="auth_mail" title="E-mail the corresponding author} ; Lena Kalinowsky^a ; ^{Kalinowsky@pharmchem.uni-frankfurt.de" class="auth_mail" title="E-mail the corresponding author} ; Jan S. Kramer^a ; ^{J.Kramer@pharmchem.uni-frankfurt.de" class="auth_mail" title="E-mail the corresponding author} ; René ; Bloecher^a ; ^{bloecher@pharmchem.uni-frankfurt.de" class="auth_mail" title="E-mail the corresponding author} ; Stefan Knapp^a ; ^{Knapp@pharmchem.uni-frankfurt.de" class="auth_mail" title="E-mail the corresponding author} ; Dieter Steinhilber^a ; ^{steinhilber@em.uni-frankfurt.de" class="auth_mail" title="E-mail the corresponding author} ; Denys Pogoryelov^b ; ^{pogoryelov@em.uni-frankfurt.de" class="auth_mail" title="E-mail the corresponding author} ; Ewgenij Proschak^a ; ^{proschak@pharmchem.uni-frankfurt.de" class="auth_mail" title="E-mail the corresponding author} ; Jan Heering^c ; ^{Jan.Heering@ime.fraunhofer.de" class="auth_mail" title="E-mail the corresponding author}
• 关键词：LTA4H ; leukotriene A4 hydrolase ; LTA4 ; leukotriene A4 ; LTB4 ; leukotriene B4 ; kDa ; kilo Dalton ; PGP ; prolin&ndash ; glycin&ndash ; prolin ; TSA ; thermal shift assay ; TM ; melting point ; ITC ; isothermal titration calorimetry ; DSF ; different scanning fluorimetry ; Ki ; inhibitory constant ; Kd ; dissoziation constant
• 刊名：Bioorganic & Medicinal Chemistry
• 出版年：2016
• 出版时间：1 November 2016
• 年：2016
• 卷：24
• 期：21
• 页码：5243-5248
• 全文大小：1412 K

文摘

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.