[CSBi-events] Friday 11/20 at 3 PM: CSB/Biophysics Seminar - Samy Meroueh

[CSBi events]

Fall 2009 Seminar Series on Computational and Systems Biology

Friday, November  20, 2009

3:00 pm - 4:00 pm

Room 32-463D

 

Presenting:

Computational Design of Molecules that Modulate Interactions Critical in
Tumor Invasion and Metastasis

                              

Professor Samy Meroueh

Department of Biochemistry and Molecular Biology and Center for
Computational Biology

Indiana University School of Medicine

 

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 http://www.biodrugscreen.org.

 

Light refreshments to be served at 2:45 pm

Host: Collin M. Stultz (cmstultz at csail.mit.edu)

 

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