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| About Charles Lesburg (Schering-Plough) |
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Dr. Charles A. Lesburg received his A.B. magna cum laude in 1991 from Harvard College, having split his undergraduate studies between synthetic organic chemistry and photography. After a year spent away from academia, he discovered that a career as a professional photographer would not be as rewarding as combining his two passions. So off he went to Philadelphia to pursue graduate work in the laboratory of Prof. David Christianson in the Chemistry Department at the University of Pennsylvania. Besides dabbling in yeast fermentation products, X-ray crystallographic studies of metalloenzymes and structure elucidation of one of the first sesquiterpene synthases cemented this synthesis of (bio)chemistry and imaging as a career. He received his Ph.D. in Biological Chemistry in 1997, and obtained a research position at the Schering-Plough Research Institute, located in Kenilworth, NJ. He is currently a Principal Scientist in the Drug Design group and continues to visualize molecules at atomic resolution in support of structure-based drug design efforts. Apart from his day job, he is the Chairman of the Industrial Macromolecular Crystallography Association (IMCA) Supervisory Board and aims to lead that consortium of pharmaceutical companies to expand the envelope and utility of industrial synchrotron data collection.
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Engineered Constitutively Active PXR Ligand Binding Domain for Inverse Structure-Based Drug Design or A Tale of Two Conformations
Charles Lesburg, Schering-Plough
The pregnane X receptor (PXR) is responsible for upregulating cytochrome P450 expression in response to a wide variety of xenobiotics. This induction of metabolism negatively impacts drug exposure and forms the basis for detrimental drug-drug interactions. We have engineered a constitutively-active PXR ligand binding domain and demonstrated that it is capable of binding known PXR ligands. Moreover, we used this construct in an inverse structure-assisted drug design effort to understand the structural basis of ligand binding to PXR. During this analysis, we were presented with unexpected binding modes which underscore the plasticity of the PXR ligand binding pocket.
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