Vern L. Schramm
Albert Einstein College of Medicine
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Primary Section: 21, Biochemistry Secondary Section: 14, Chemistry Membership Type:
Member
(elected 2007)
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Research Interests
All chemical reactions pass through an energetic barrier called the transition state, where the probability of return to reactants and conversion to products is equal. We know little about transition states since their lifetimes are on the time scale of a single bond vibration. Despite these difficulties, the systematic application of kinetic isotope effects, together with computational approaches, can define the chemical nature of transition state structures. Our interests are in analysis of transition state structures for enzyme-catalyzed reactions using the process we call transition state analysis. The molecular electrostatic features of enzymatic transition states are established and used to design analogues of enzymatic transition states. Mimics of enzymatic transition states capture the catalytic power of enzymes and covert it into ligand binding energy to create powerful inhibitors. We have solved the transition state structures of drug target enzymes and have synthesized some of the most powerful known enzymatic inhibitors. Several of these are in clinical trials for human diseases. Application of transition state theory to targeted enzymes has the potential to revolutionize drug design. A related interest of the laboratory is binding isotope effects. This method reports on bond electronic distortion as ligands bind to receptors. In summary, we strive to understand details of enzymatic catalysis and to apply those to inhibitor design.
