The principal research interest of the Hamilton group is in the field of molecular recognition and its application to problems in organic and biological chemistry.
- Artificial Receptor Design
- Catalyst Development
- Enzyme Inhibition
- Peptidomimetic Design
- Proteomimetic Design
- Disruption of Protein-Protein Interactions
- Modulation of Signal Transduction
The Hamilton group's early work focused on controlling intermolecular interactions through precisely positioned hydrogen bonding groups. The first excursion into this area came through studies on the antibiotic vancomycin. The Hamilton group was the first to design molecules with shapes and hydrogen bonding patterns based on the natural antibiotic that were able to complex carboxylate derivatives in a similar manner. The search for simple solutions to the vancomycin problem led them to develop a family of aminopyridine and related derivatives as host molecules for a range of target substrates. These advances included the synthesis of receptors for barbiturates, carboxylic acids, nucleotide bases, flavins, phosphodiesters, carbohydrates and amino acids. The precise detail with which these recognition interactions could be analyzed both in solution and the solid state led to new insights into the role of hydrogen bonding and p-stacking interactions in molecular recognition. These studies on hydrogen bonding and p-stacking form the basis of another important area in the Hamilton group 's work, namely the design of artificial enzymes. Using the cis-trans isomerization of acylproline as a model, Hamilton's group demonstrated that synthetic receptors could selectively complex one isomer in a conformational equilibrium. Later work showed that selectivity for high-energy intermediates or transition states on a reaction pathway can be built into synthetic receptors. Using this strategy The Hamilton group has shown large accelerations in a number of reactions important in both organic and biological chemistry, including the Diels-Alder reaction, phosphate ester hydrolysis, and transacylation, as well as photoinduced energy transfer in multichromophore aggregates.
Protein Surface Recognition
A major recent area of research for the Hamilton group focuses on the design of synthetic agents that bind and recognize the exterior surfaces of proteins. In particular, they have shown that hydrophobic interactions can be used to stabilize a-helices and by designing non-peptidic oligomers (foldamers) that fold into extended sheet or helical conformations. The group has further demonstrated that small synthetic receptors that complement the functional groups on an a-helix surface can bind in a sequence and secondary structure selective fashion. A new class of synthetic receptors based on the multiple peptide loop structure of antibody combining sites has been prepared and shown not only to bind strongly to protein surfaces but also to block their interaction with both chemical reagents and their natural protein partners. This has led to a new concept in enzyme inhibitor design in which the exterior of the protein instead of the active site is targeted and a new family of potent antiproliferative agents that block the interaction of growth factors with their cell surface receptors in animal models of human cancer.