6 research outputs found
Dual-Target Virtual Screening by Pharmacophore Elucidation and Molecular Shape Filtering
Dual-target inhibitors gained increased attention in
the past years.
A novel in silico approach was employed for the discovery of dual
5-lipoxygenase/soluble epoxide hydrolase inhibitors. The ligand-based
approach uses excessive pharmacophore elucidation and pharmacophore
alignment in conjunction with shape-based scoring. The virtual screening
results were verified in vitro, leading to nine novel inhibitors including
a dual-target compound
Approved Drugs Containing Thiols as Inhibitors of Metallo-β-lactamases: Strategy To Combat Multidrug-Resistant Bacteria
Resistance
to β-lactam antibiotics can be mediated by metallo-β-lactamase
enzymes (MBLs). An MBL inhibitor could restore the effectiveness of
β-lactams. We report on the evaluation of approved thiol-containing
drugs as inhibitors of NDM-1, VIM-1, and IMP-7. Drugs were assessed
by a novel assay using a purchasable fluorescent substrate and thermal
shift. Best compounds were tested in antimicrobial susceptibility
assay. Using these orthogonal screening methods, we identified drugs
that restored the activity of imipenem
Synthesis and Structure–Activity Relationship Studies of Novel Dual Inhibitors of Soluble Epoxide Hydrolase and 5‑Lipoxygenase
Current research leads to the assumption that drugs affecting
more
than one target could result in a more efficient treatment of diseases
and fewer safety concerns. Administration of drugs inhibiting only
one branch of the arachidonic acid cascade is usually accompanied
by side effects. We therefore designed and synthesized a library of
hybrid molecules incorporating an imidazo[1,2-<i>a</i>]pyridine
and an urea moiety as novel soluble epoxide hydrolase (sEH)/5-lipoxygenase
(5-LO) dual inhibitors. Evaluation of the compounds was accomplished
by in vitro testing using recombinant enzyme assays
Discovery of the First in Vivo Active Inhibitors of the Soluble Epoxide Hydrolase Phosphatase Domain
International audienceThe emerging pharmacological target soluble epoxide hydrolase (sEH) is a bifunctional enzyme exhibiting two different catalytic activities that are located in two distinct domains. Although the physiological role of the C-terminal hydrolase domain is well-investigated, little is known about its phosphatase activity, located in the N-terminal phosphatase domain of sEH (sEH-P). Herein we report the discovery and optimization of the first inhibitor of human and rat sEH-P that is applicable in vivo. X-ray structure analysis of the sEH phosphatase domain complexed with an inhibitor provides insights in the molecular basis of small-molecule sEH-P inhibition and helps to rationalize the structure−activity relationships. 4-(4-(3,4-Dichlorophenyl)-5-phenyloxazol-2-yl)butanoic acid (22b, SWE101) has an excellent pharmacokinetic and pharmacodynamic profile in rats and enables the investigation of the physiological and pathophysiological role of sEH-P in vivo
Challenges in the Development of a Thiol-Based Broad-Spectrum Inhibitor for Metallo-β-Lactamases
Pathogens, expressing metallo-β-lactamases
(MBLs), become resistant against most β-lactam antibiotics.
Besides the dragging search for new antibiotics, development of MBL
inhibitors would be an alternative weapon against resistant bacterial
pathogens. Inhibition of resistance enzymes could restore the antibacterial
activity of β-lactams. Various approaches to MBL inhibitors
are described; among others, the promising motif of a zinc coordinating
thiol moiety is very popular. Nevertheless, since the first report
of a thiol-based MBL inhibitor (thiomandelic acid) in 2001, no steps
in development of thiol based MBL inhibitors were reported that go
beyond clinical isolate testing. In this study, we report on the synthesis
and biochemical characterization of thiol-based MBL inhibitors and
highlight the challenges behind the development of thiol-based compounds,
which exhibit good <i>in vitro</i> activity toward a broad
spectrum of MBLs, selectivity against human off-targets, and reasonable
activity against clinical isolates
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Discovery of the First in Vivo Active Inhibitors of the Soluble Epoxide Hydrolase Phosphatase Domain
The emerging pharmacological target soluble epoxide hydrolase (sEH) is a bifunctional enzyme exhibiting two different catalytic activities that are located in two distinct domains. Although the physiological role of the C-terminal hydrolase domain is well-investigated, little is known about its phosphatase activity, located in the N-terminal phosphatase domain of sEH (sEH-P). Herein we report the discovery and optimization of the first inhibitor of human and rat sEH-P that is applicable in vivo. X-ray structure analysis of the sEH phosphatase domain complexed with an inhibitor provides insights in the molecular basis of small-molecule sEH-P inhibition and helps to rationalize the structure-activity relationships. 4-(4-(3,4-Dichlorophenyl)-5-phenyloxazol-2-yl)butanoic acid (22b, SWE101) has an excellent pharmacokinetic and pharmacodynamic profile in rats and enables the investigation of the physiological and pathophysiological role of sEH-P in vivo