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

Abstract

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.

Next generation 3D pharmacophore modeling

“…In a first step, they virtually screened the SPECS library with two different ligand‐based pharmacophore models both derived from known FLA protein inhibitors. Twenty selected hit molecules were further prioritized by previously reported structure‐based sHE models and resulted in one novel and potent dual FLA protein/sHE inhibitor . Since multitarget approaches are getting more and more attention, this example shows that ligand‐based pharmacophores could have some benefits when applying on multiple targets that bind chemically similar physiological ligands.…”

Cytochrome P450 eicosanoids in cerebrovascular function and disease

“…The drug increased forearm blood flow in response to bradykinin in overweight smokers, which is blunted compared to control group, demonstrating improved endothelial function, therefore demonstrating promising viability for further testing (Lazaar et al, 2015; Yang et al, 2017). Further sEH inhibitor drug discovery is ongoing, with the identification of further drugs, both peripherally restricted, as well as peripherally and centrally active, already identified, as well as virtual screening to identify new drugs, potentially leading to future clinical trials (McReynolds et al, 2016; Waltenberger et al, 2016). The multiple therapeutic applications of inhibitors of sEH have been reviewed (Shen and Hammock, 2012).…”

Exported Epoxide Hydrolases Modulate Erythrocyte Vasoactive Lipids during Plasmodium falciparum Infection

“…Promoting a “quiescent” endothelium and normal vasoreactivity would be disadvantageous to the parasite, as fewer endothelial adhesins displayed would result in less cytoadherence and increased splenic clearance of parasitized RBCs. Multiple EH inhibitors are in development (67, 80, 81), with several currently in clinical trials (ClinicalTrials.gov identifier [ID] NCT00847899, NCT01762774, and NCT02006537). If epoxy signaling lipids are important for reducing P. falciparum virulence in vivo , there is also a possibility that these inhibitors may be repurposed as antimalarials.…”