TITLE:

ESTABLISHMENT OF A STRUCTURE REACTIVITY RELATIONSHIP FOR SPHINGOMYELINASE INHIBITORS (No. 90)

DATE:

Friday, October 7th, 2005

TIME:

3:30 PM

LOCATION:

GMCS 214

SPEAKER:

Thomas Cole, Department of Chemistry, San Diego State University

ABSTRACT:

Sphingomyelinase inhibitors are attractive drug targets for the treatment of heart attacks and strokes. Currently, there are no approved drugs that inhibit this enzyme which initiates signal transduction and cell death via apoptosis in cardiomyocytes and neuron cells. Inhibitors of this sphingomyelin may also prove valuable for the development of new therapies of various inflammatory and autoimmune diseases. The target protein, neutral sphingomyelinase, nSMase, is a membrane bound enzyme. As a consequence, these enzymes do not readily form well-ordered crystals suitable for X-ray structures. Alternatively, a comparison of biological activity versus structurally related inhibitors, gives a Structure Activity Relationship (SAR). This SAR gives binding information of the drugs to the active site, guiding the identification of even more active inhibitors. Molecular modeling is used extensively throughout our drug discovery program. These calculations have allowed us to develop more selective and general reactions in the formation of the drug precursors used in this SAR study. Modeling is also used to predict potential structures of the neutral sphingomyelinase based on other similar known protein structures. The qualitative structure active relationship is then used to examine how these inhibitors bind to the active site, aiding the identification of the next generation of more active and selective inhibitors.

HOST:

Paul Paolini

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