Concepts for Engineering Drugs

Jeremy C. Smith, Chair at the University of Tennessee, Director of the UT/ORNL Center for Molecular Biophysics, Oak Ridge National Laboratory
When Oct 30, 2015
from 01:00 PM to 02:15 PM
Where Ernst Hall, Room 310
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Abstract

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.

Speaker's Biography

From 1985-1989: Jeremy Smith worked as a post-doctoral associate and lecturer at Harvard University in the group of Nobel Laureate Martin Karplus.
Smith has since built up research groups in three different countries. His first group was in Biomolecular Simulation at the Commissariat à l'énergie atomique (CEA) at Saclay, France (1989–1998). He then became the first chaired professor in computational biology in Germany, when appointed at the Interdisciplinary Center for Scientific Computing of the University of Heidelberg, Germany in 1998.

In October 2006 Smith became the first Governor's Chair at the University of Tennessee and also Director of the UT/ORNL Center for Molecular Biophysics at Oak Ridge National Laboratory. His move to Tennessee arose from the presence at ORNL of world-class supercomputing capabilities and the Spallation Neutron Source, as the combination of neutron scattering with computer simulation has been a sustained interest of his. In 2008, Smith was appointed Honorarprofessor (i.e., honorary professor) at the University of Heidelberg.