Dataset Information

Design of Dual Inhibitors of Soluble Epoxide Hydrolase and LTA₄ Hydrolase.

ABSTRACT: Multitarget anti-inflammatory drugs interfering with the arachidonic acid cascade exhibit superior efficacy. In this study, a prototype dual inhibitor of soluble epoxide hydrolase (sEH) and LTA₄ hydrolase (LTA₄H) with submicromolar activity toward both targets has been designed and synthesized. Preliminary structure-activity relationship studies were performed to identify optimal substitution patterns. X-ray structure analysis of a promising dual inhibitor in complex with sEH, as well as molecular docking with LTA₄H provided a rationale for further optimization. Hereby, scaffold extension was successfully applied to yield potent dual sEH/LTA₄H inhibitors. The spectrum of pro- and anti-inflammatory lipid mediators was evaluated in M1 and M2 macrophages, stimulated with LPS, and incubated with the most promising compound 14. The effect of 14 on the inflammatory lipid mediator profile characterizes dual sEH/LTA₄H inhibitors as an interesting option for future anti-inflammatory agent investigations.

SUBMITTER: Hiesinger K

PROVIDER: S-EPMC7073873 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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Publications

Design of Dual Inhibitors of Soluble Epoxide Hydrolase and LTA4 Hydrolase.

Hiesinger Kerstin K Schott Annika A Kramer Jan S JS Blöcher René R Witt Finja F Wittmann Sandra K SK Steinhilber Dieter D Pogoryelov Denys D Gerstmeier Jana J Werz Oliver O Proschak Ewgenij E

ACS medicinal chemistry letters 20191030 3

Multitarget anti-inflammatory drugs interfering with the arachidonic acid cascade exhibit superior efficacy. In this study, a prototype dual inhibitor of soluble epoxide hydrolase (sEH) and LTA4 hydrolase (LTA4H) with submicromolar activity toward both targets has been designed and synthesized. Preliminary structure-activity relationship studies were performed to identify optimal substitution patterns. X-ray structure analysis of a promising dual inhibitor in complex with s ...[more]

PMID: 32184960

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Project description:Human soluble epoxide hydrolase (sEH), a dual-functioning homodimeric enzyme with hydrolase and phosphatase activities, is known for its pivotal role in the hydrolysis of epoxyeicosatrienoic acids. Inhibitors targeting sEH have shown promising potential in the treatment of various life-threatening diseases. In this study, we employed a range of in silico modeling approaches to investigate a diverse dataset of structurally distinct sEH inhibitors. Our primary aim was to develop predictive and validated models while gaining insights into the structural requirements necessary for achieving higher inhibitory potential. To accomplish this, we initially calculated molecular descriptors using nine different descriptor-calculating tools, coupled with stochastic and non-stochastic feature selection strategies, to identify the most statistically significant linear 2D-QSAR model. The resulting model highlighted the critical roles played by topological characteristics, 2D pharmacophore features, and specific physicochemical properties in enhancing inhibitory potential. In addition to conventional 2D-QSAR modeling, we implemented the Transformer-CNN methodology to develop QSAR models, enabling us to obtain structural interpretations based on the Layer-wise Relevance Propagation (LRP) algorithm. Moreover, a comprehensive 3D-QSAR analysis provided additional insights into the structural requirements of these compounds as potent sEH inhibitors. To validate the findings from the QSAR modeling studies, we performed molecular dynamics (MD) simulations using selected compounds from the dataset. The simulation results offered crucial insights into receptor-ligand interactions, supporting the predictions obtained from the QSAR models. Collectively, our work serves as an essential guideline for the rational design of novel sEH inhibitors with enhanced therapeutic potential. Importantly, all the in silico studies were performed using open-access tools to ensure reproducibility and accessibility.

Dataset Information

Design of Dual Inhibitors of Soluble Epoxide Hydrolase and LTA₄ Hydrolase.

Publications

Design of Dual Inhibitors of Soluble Epoxide Hydrolase and LTA<sub>4</sub> Hydrolase.

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