4:00PM MIT Building 4, Room 163
Prof. Jeremy Smith
UT/
Oak
Ridge Natl. Lab.
Concepts Of Protein Dynamics In Drug Design
The design of drugs using protein structures is undergoing a renaissance.
Now, internal motions of proteins have begun to be incorporated into
structure-based drug development. We examine the variety of motions in
proteins, demonstrate entropy-driven vibrational softening on the binding
of a cancer drug to its target and show that inter-domain motion can be
described by the principle of De Gennes Narrowing. Curiously, over the
typical biological lifespan of a protein internal motions remain out of
equilibrium, obeying a self-similar (fractal) time dependence over thirteen
decades in time. Metastability analysis can be used to produce a
thermodynamically rigorous representation of the conformational transitions
involved. Finally, we show how the incorporation of protein dynamics into
virtual high-throughput screening has permitted the successful generation
of lead compounds to combat hypophosphatemia, antibiotic resistance and
thrombosis.
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Adrian Jinich
Aspuru-Guzik Lab
Harvard University
12 Oxford Street
Cambridge, MA 02138
ajinich(a)fas.harvard.edu
http://aspuru.chem.harvard.edu/adrian-jinich/