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)