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Design of soluble epoxide hydrolase inhibitors as drug leads

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.

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Design of soluble epoxide hydrolase inhibitors as drug leads

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  1. Design of soluble epoxide hydrolase inhibitors as drug leads Junghwa Kim, Elise Pellmann, Mike Wild Daniel Sem, Ph.D. John Imig, Ph.D.

  2. sEH: biology • Epoxyeicosatrienoic acids (EETs) • Cytochrome P450 • Vasodilation, anti-inflammatory, angiogenesis • sEH inhibition

  3. sEH: biochemistry Two domains: hydrolase (N-terminal), phosphatase (C-terminal)

  4. sEH As a Teaching ExampleHydrolysis of Epoxides, Enzyme Activity, Catalytic Triad

  5. 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

  6. Inhibitor Design • Study of 1VJ5 Crystal Structure • Jmol and Swiss Viewer • Propose Drug Leads • Draw in ChemDraw From Swiss Viewer

  7. Inhibitor Design • Draw Structure of Drugs in Spartan • Place designed drugs on Enzyme (sEH) through Discovery Studio Visualizer

  8. What’s next? • Kinetic assays (in vitro): Determine Kd, mode of inhibition • ADMET (in vivo, in silico) In silico: docking, TOPKAT (accelrys)

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