Highaffinity Ligands

Production of HALs currently requires that the protein structure be known experimentally. The surface is manually inspected by experts using programs such as DOCK (http://www.cmpharm.ucsf.edu/kuntz/dock.html) to identify suitable-sized surface depressions or pockets. A large library of synthetic molecules is then compared against the pocket shape, looking for a potential "fit." Potential fits are further examined for features such as charge, hydrophobic-ity, etc. that could preclude them from successful binding. Synthetic chemistry is used to create the best candidates, which are then tested against the target protein. This process has been used to create HALs that recognize various pathogen toxins, as seen in Figure 15.1.

At LLNL we are exploring several ways to scale up this process. First, as described below, we have improved protein structure modeling so that HAL design can be attempted without an experimentally solved structure. Second, we are investigating faster methods for locating suitable pockets. Finally, we plan to incorporate large supercomputers to speed up checking of the small

FIGURE 15.1 A representation of a bi-dentate ligand that recognizes the botulinum toxin. Figure courtesy of Rod Balhorn, LLNL. (See color insert.)

molecule libraries against each potential HAL pocket. Other similar efforts are underway, and it is hoped that a major acceleration of protein detection diagnostics can be achieved within a few years.

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