Discovery of Potent Soluble Epoxide Hydrolase (sEH) Inhibitors by Pharmacophore-Based Virtual Screening

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• 作者：Birgit Waltenberger ; Ulrike Garscha ; Veronika Temml ; Josephine Liers ; Oliver Werz ; Daniela Schuster ; Hermann Stuppner
• 刊名：Journal of Chemical Information and Modeling
• 出版年：2016
• 出版时间：April 25, 2016
• 年：2016
• 卷：56
• 期：4
• 页码：747-762
• 全文大小：954K
• 年卷期：0
• ISSN：1549-960X

文摘

There is an increasing interest in the development of soluble epoxide hydrolase (sEH) inhibitors, which block the degradation of endogenous anti-inflammatory epoxyeicosatrienoic acids. Within this study, a set of pharmacophore models for sEH inhibitors was developed. The Specs database was virtually screened and a cell-free sEH activity assay was used for the biological investigation of virtual hits. In total, out of 48 tested compounds, 19 were sEH inhibitors with IC₅₀ < 10 μM, representing a prospective true positive hit rate of 40%. Six of these compounds displayed IC₅₀ values in the low nanomolar range. The most potent compound 21, a urea derivative, inhibited sEH with an IC₅₀ = 4.2 nM. The applied approach also enabled the identification of diverse chemical scaffolds, e.g. the pyrimidinone derivative 29 (IC₅₀ = 277 nM). The generated pharmacophore model set therefore represents a valuable tool for the selection of compounds for biological testing.