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<p class=MsoNormal><o:p> </o:p></p>
<p class=MsoNormal><b>Fall 2009 Seminar Series on Computational and Systems
Biology<o:p></o:p></b></p>
<p class=MsoNormal>Friday, November 20, 2009<o:p></o:p></p>
<p class=MsoNormal>3:00 pm – 4:00 pm<o:p></o:p></p>
<p class=MsoNormal>Room 32-463D<o:p></o:p></p>
<p class=MsoNormal><o:p> </o:p></p>
<p class=MsoNormal>Presenting:<o:p></o:p></p>
<p class=MsoPlainText><b><span style='font-size:11.0pt;font-family:"Calibri","sans-serif"'>Computational
Design of Molecules that Modulate Interactions Critical in Tumor Invasion and
Metastasis<o:p></o:p></span></b></p>
<p class=MsoNormal>
<o:p></o:p></p>
<p class=MsoNormal>Professor Samy Meroueh<o:p></o:p></p>
<p class=MsoPlainText><span style='font-size:11.0pt;font-family:"Calibri","sans-serif"'>Department
of Biochemistry and Molecular Biology and Center for Computational Biology<o:p></o:p></span></p>
<p class=MsoPlainText><span style='font-size:11.0pt;font-family:"Calibri","sans-serif"'>Indiana
University School of Medicine<o:p></o:p></span></p>
<p class=MsoNormal> <o:p></o:p></p>
<p class=MsoPlainText><span style='font-size:11.0pt;font-family:"Calibri","sans-serif"'>The
urokinase receptor (uPAR) is a GPI-anchored cell surface receptor that focuses
proteolysis at the cell surface through its association with the serine
protease urokinase (uPA). In addition, uPAR activates cell surface
receptors that include integrins, receptor tyrosine kinases (RTKs) and
G-coupled protein receptors (GPCRs). A large body of evidence has
implicated these interactions with tumor invasion and metastasis. A
computational search through molecular docking is conducted to target multiple
sites on uPAR in an effort to simultaneously shut down its proteolytic and
signaling capabilities. A number of molecules were found to bind to the
receptor as established through biochemical assays. In cell culture,
compounds revealed inhibition of MDA-MB-231 breast tumor cell adhesion,
migration, invasion, angiogenesis and proliferation. Extensive sampling
of uPAR conformational states through explicit solvent atomistic simulations
followed by free energy calculations revealed that uPAR can be allosterically
modulated. Based on these results we followed a multi-conformer docking
approach to target alternative sites on the receptor and identify allosteric
modulators of the receptor. Among the top candidates, a number of
molecules were found to inhibit binding in vitro despite the distal nature of
the targeted site. Finally, I describe our efforts at docking molecules
to the human proteome in a multi-targeted approach to drug discovery and the
creation of an online drug screening resource at <a
href="http://www.biodrugscreen.org">http://www.biodrugscreen.org</a>.<o:p></o:p></span></p>
<p class=MsoNormal><o:p> </o:p></p>
<p class=MsoNormal>Light refreshments to be served at 2:45 pm<o:p></o:p></p>
<p class=MsoPlainText><span style='font-size:11.0pt;font-family:"Calibri","sans-serif"'>Host:
Collin M. Stultz (cmstultz@csail.mit.edu)<o:p></o:p></span></p>
<p class=MsoNormal><o:p> </o:p></p>
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