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Design of soluble epoxide hydrolase inhibitors as drug leads. Junghwa Kim, Elise Pellmann, Mike Wild Daniel Sem, Ph.D. John Imig, Ph.D. sEH: biology. Epoxyeicosatrienoic acids (EETs) Cytochrome P450 Vasodilation, anti-inflammatory, angiogenesis. sEH inhibition. sEH: biochemistry. - PowerPoint PPT Presentation
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Design of soluble epoxide hydrolase inhibitors as drug leads
Junghwa Kim, Elise Pellmann, Mike WildDaniel Sem, Ph.D. John Imig, Ph.D.
sEH: biology• Epoxyeicosatrienoic acids (EETs) • Cytochrome P450• Vasodilation, anti-inflammatory, angiogenesis
• • sEH inhibition
EETs sEH DHETs
sEH: biochemistry
• Two domains: hydrolase (N-terminal), phosphatase (C-terminal)
sEH As a Teaching ExampleHydrolysis of Epoxides, Enzyme Activity, Catalytic Triad
OO-
ASP176
NN
O
H
SER152HIS263
ORR'
O O-
OR
O
R"
SER152
Triacylglyceral Tetrahedralintermediate@2005 John McMurry
O
O
H
OO-
ASP495
NN
O
H
H
HIS523
H
OH
ASP333
O
OH
ASP333
O-
HO
Tetrahedralintermediate
Acyl enzyme
HIS523
Diol
Chem. Eur. J. 2006, 12 6899
HIS263
O H+
HO
OH
Hydrolysis of Epoxides
OH-
Human pancreatic lipase
Soluble epoxide hyrolase
Imig Group Experiment
• Development of EET Analogs• Studied Male Rats
– Renal Effects– Blood Pressure/Heart Rate
• Most Promising Lead- 11,12-ether-EET-8-ZE
O
OH
O
11,12-Ether-EET-8-ZE
Inhibitor Design
• Study of 1VJ5 Crystal Structure– Jmol and Swiss Viewer
• Propose Drug Leads• Draw in ChemDraw
OH
HN
HN
O
From Swiss Viewer
Try381
HO
Try465
OH
-O O-
1
Asp333
2.86
5.45
3.60
HN
Trp334
4.50
Inhibitor Design
• Draw Structure of Drugs in Spartan• Place designed drugs on Enzyme (sEH)
through Discovery Studio Visualizer
What’s next?
• Kinetic assays (in vitro): Determine Kd, mode of inhibition
• ADMET (in vivo, in silico)In silico: docking, TOPKAT (accelrys)