Structure-based drug design with Soluble Epoxide Hydrolase

Summary

Soluble Epoxide Hydrolase (sEH), and more importantly its inhibition, may form the basis of a number of therapies due to anti-inflammatory

Supervisor(s)

Dr W Bret Church

Research Location

Faculty of Pharmacy

Program Type

PHD

Synopsis

The arachidonic acid cascase is targeted in 70% of pharmaceuticals. Epoxyeicosatrienoic acids (EETs) are in the cascade and are among the anti-inflammatory metabolites of the cascade with a variety of biological effects. Retaining these metabolites can be achieved by way of increasing EET concentrations through either exogenous delivery or by stabilizing EETs via inhibition of soluble epoxy hydrolase (sEH). The potential role of the sEH is in part due to its existence in the liver, kidney and vascular tissue. As arachidonic acid is released in response to tissue injury the arachidonic acid cascade is invoked in many disease states, with resulting consequences in diabetes, atheroschlerosis, inflammation (including chronic lung disorders), hypertension, and cancer. Many animal experiments have demonstrated the potential for sEH inhibitors, and there are results on the amelioration of pain and inflammation, for instance. Large scale production of sEHs will be pursued using heterologous expression in insect cells, to obtain the protein required for crystallization studies. We have access to hundred of inhibitors that have IC50 in the nanomolar range. Pure protein is required for crystallization, which allows determination of the crystallographic structure of the enzyme with the inhibitors. As extensive as the inhibitor list is, virtual screening and fragment based screening may be used to look for more lead compounds. These efforts are part of the strategies for the rational design of more useful inhibitors of sEH.

Additional Information

Techniques used will be HPLC, X-ray crystallography, isothermal calorimetry, molecular biology, molecular modeling, protein purification, fragment screening

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Keywords

Crystallisation, protein, complex, structure, drug design, inhibitors, rational drug design, inflammation, Pain, atherosclerosis, Cancer

Opportunity ID

The opportunity ID for this research opportunity is: 1143

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