Thermodynamic properties of leukotriene A 4 hydrolase inhibitors

Wittmann, Sandra K.; Kalinowsky, Lena; Kramer, Jan S.; Bloecher, René; Knapp, Stefan; Steinhilber, Dieter; Pogoryelov, Denys; Proschak, Ewgenij; Heering, Jan

doi:10.1016/j.bmc.2016.08.047

Cited by 12 publications

(19 citation statements)

References 21 publications

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“… Isothermal titration calorimetry (ITC) confirmed binding of 8 and 19 to the recombinant human FXR LBD [29] and to recombinant human LTA4H. [30] 1:1 binding was assumed. …”

Section: Resultsmentioning

confidence: 95%

“…We have previously shown that the interaction with this hydrophobic tunnel plays a critical role in ligand binding to LTA4H. [30] While the lipophilic tunnel can accept various alkoxy and phenoxy substituents, rigid moieties as present, for example, in 12 are not favored. In addition to the Zn 2+ ‐interaction and occupation of the lipophilic tunnel, the amide carbonyl oxygen of 19 engages a directed H‐bond towards Gln134, while the NH is oriented towards the electron‐rich Tyr378.…”

Section: Resultsmentioning

confidence: 99%

“…The alkoxy motif of 19 points towards the hydrophilic tunnel. We have previously shown that the interaction with this hydrophobic tunnel plays a critical role in ligand binding to LTA4H [30] . While the lipophilic tunnel can accept various alkoxy and phenoxy substituents, rigid moieties as present, for example, in 12 are not favored.…”

Section: Resultsmentioning

confidence: 99%

“…The results of three different experiments were analyzed using GraphPad Prism 7 by transforming the concentration to logarithmic values and using the “log(inhibitor) vs. normalized response‐variable slope” fit to determine IC 50 values. Bestatin (IC 50 0.30±0.01 μM) served as reference LTA4H inhibitor [30] …”

Section: Methodsmentioning

confidence: 99%

“…Pure protein in buffer (50 mM Tris, 50 mM NaCl, pH=8) was frozen in liquid nitrogen and stored at −80 °C. A fluorescence‐based LTA4H enzyme activity assay was performed using this recombinant protein according the published protocol [30] by Wittmann et al. with L‐arginine‐7‐amino‐4‐methylcoumarine (Sigma Aldrich) as fluorogenic substrate which is cleaved by LTA4H to L‐arginine and fluorescent 7‐amino‐4‐methylcoumarine.…”

Section: Methodsmentioning

confidence: 99%

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Development and in vitro Profiling of Dual FXR/LTA4H Modulators

et al. 2021

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Designed polypharmacology presents as an attractive strategy to increase therapeutic efficacy in multi‐factorial diseases by a directed modulation of multiple involved targets with a single molecule. Such an approach appears particularly suitable in non‐alcoholic steatohepatitis (NASH) which involves hepatic steatosis, inflammation and fibrosis as pathological hallmarks. Among various potential pharmacodynamic mechanisms, activation of the farnesoid X receptor (FXRa) and inhibition of leukotriene A4 hydrolase (LTA4Hi) hold promise to counteract NASH according to preclinical and clinical observations. We have developed dual FXR/LTA4H modulators as pharmacological tools, enabling evaluation of this polypharmacology concept to treat NASH and related pathologies. The optimized FXRa/LTA4Hi exhibits well‐balanced dual activity on the intended targets with sub‐micromolar potency and is highly selective over related nuclear receptors and enzymes rendering it suitable as tool to probe synergies of dual FXR/LTA4H targeting.

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“… Isothermal titration calorimetry (ITC) confirmed binding of 8 and 19 to the recombinant human FXR LBD [29] and to recombinant human LTA4H. [30] 1:1 binding was assumed. …”

Section: Resultsmentioning

confidence: 95%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

See 3 more Smart Citations