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| About Heather Carlson (University of Michigan) |
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Heather A. Carlson graduated Magna Cum Laude from North Central College in Naperville, IL with a B.S. in Mathematics, Chemistry, and Physics. She received her M.S. and Ph.D. under the tutelage of William L. Jorgensen at Yale University. She received postdoctoral fellowships from the American Cancer Society and the Burroughs Wellcome Fund program, La Jolla Interfaces in Science, to study protein simulations and computational biology withJ. Andrew McCammon at the University of California, San Diego. In 2000, Carlson began her academic career at the University of Michigan, Ann Arbor as the John Gideon Searle Assistant Professor of Medicinal Chemistry. She is now an Associate Professor in Michigan's College of Pharmacy. She also has editorial duties for three scientific journals. Carlson received a Beckman Young Investigator Award in 2002, an NSF CAREER Award in 2006, and her College's Teaching Excellence Award in 2007. Her research broadly addressesprotein-ligand interactions, from the basic biophysics of molecular recognition to applied inhibitor design. Funding from the NIH has allowed her to develop her technique for incorporating protein flexibility into drug discovery. Funding from the Beckman Foundation and the NSF has allowed her group to create Binding MOAD (Mother of All Databases),the largest collection of protein-ligand complexes with binding data.
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Fundamental differences between high- and low-affinity complexes of enzymes and non-enzymes
Heather A. Carlson, University of Michigan
Stark differences between enzymes and non-enzymes were found through mining the protein-ligand database, Binding MOAD (Mother of All Databases, pronounced "mode" as a pun on the ligand's mode of binding to its protein target). Ligand efficiencies were found to be much higher in non-enzymes. Every atom, every square Ångstrom of contact gives more free energy in non-enzymatic binding sites. This implies they may be more "druggable" targets than enzymes because drug-like affinities can be obtained with smaller molecules which are more easily absorbed and have less functional groups for potential toxicity concerns. Additional data also suggest that divergent approaches may be needed to improve the affinity of ligands for the two classes of proteins. High-affinity ligands are much larger than low-affinity ligands for enzyme complexes. The addition of complementary functional groups is likely to improve the affinity of an enzyme inhibitor through more contact with the pocket, but this process may not be as fruitful for ligands of non-enzymes. High- and low-affinity inhibitors are the same size in non-enzymes. The inherent differences between enzymes and non-enzymes have significant ramifications for scoring functions and structure-based drug design.
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