Most pharmaceuticals are small molecules that bind to concavities in large molecular target sites. The scarcity of drugs that act like binding pockets (e.g., Vancomycin) is not an indication of their lack of utility: antibodies, for example, are very useful. However, chemistry lags in its ability to design useful smaller, simpler binding pockets. The ability to target a small molecule or arbitrary location on an enzyme or receptor would increase the strategies available for pharmaceutical development. Long term objectives of my research are to design and prepare synthetic antibody-like binding sites and enzyme-like catalysts with predetermined specificity. We propose here a family of host molecules, each assembled or organized by a metal, to bind polyfunctional organic guests. The metals provide effective methods for building complex structures rapidly, controlling their shapes and presentation of functional groups, and making small perturbations to the structures. A key to selectivity is the cooperation of multiple binding interactions. As measured by effective molarity (EM) values, our receptors are outstanding. We plan to probe the generality of these large EM values. This will lead to interesting and useful receptors, as well as to an increased appreciation of the significance of these factors in natural systems.
Specific aims : 1. To generalize and characterize further the self- assembled metal complexes that we have shown will ditopically bind guests. As we modify metals and ligands, we will evaluate the effect on these EM values, which will assist our ability to design a specific binding site. 2. To demonstrate molecular templating for stereochemical control of the construction of well defined host molecules.
We aim to demonstrate control of cavity shape, as well as of orientation of binding groups and appendages.
| Valentine, Stephen J; Liu, Xiaoyun; Plasencia, Manolo D et al. (2005) Developing liquid chromatography ion mobility mass spectometry techniques. Expert Rev Proteomics 2:553-65 |
| Liu, Xiaoyun; Plasencia, Manolo; Ragg, Susanne et al. (2004) Development of high throughput dispersive LC-ion mobility-TOFMS techniques for analysing the human plasma proteome. Brief Funct Genomic Proteomic 3:177-86 |
