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CHEMISTRY/PHARMACOLOGY
Combinatorial chemistry is now being used to generate focused, targeted libraries of compounds based on novel chemical backbones
Until the introduction of solid-phase synthesis in 1963, organic chemists thought and worked linearly. Over the next three decades, demand for chemical diversity spawned methods for generating chemical variations on a theme, in parallel and for almost any quantity, almost at the push of a button. Interest in chemical "numbers" reached a fever pitch by 1995, by which time an industry had sprung up around million-compound libraries.
"Combinatorial chemistry hasn't yet led to an expected flood of new drugs, but it's an exciting technique that's adding new dimensions to chemistry," says Arno Spatola, PhD, a chemist who directs the University of Louisville's Institute for Molecular Diversity and Drug Design, Louisville, Ky.
Louisville is home to at least three companies that evolved from the university's research expertise. Peptides International Inc. (peptides, enzyme inhibitors, combichem supplies), Advanced ChemTech Inc. (parallel synthesis instrumentation), and Advanced SynTech (laboratory robotics).
"Parallel methods are still most useful for searching for leads via high-throughput screens when no x-ray or homology structure data for a target is available," says Spatola. "Industry is shying away from using very large mixtures, although a few of us in academia still feel there is a place for large libraries containing up to one million compounds per mixture, as long as proper precautions are taken."
Spatola's inclination toward large libraries and combinatorial synthesis is due, in part, to his focus on cyclic peptide and pseudopeptide libraries. Next to oligonucleotides, peptides are perhaps the easiest molecules to make in massively parallel fashion on solid support. "Multiple-reaction parallel synthesizers make it easy to synthesize large numbers of individual compounds, which eliminates part of the problem of deconvolution: finding the needle in the haystack. Our latest versions are individual compounds or smaller mixtures, though with representation of both D and L versions of the amino acids. The latest trend is to try to use various algorithms to try to prescreen classes of compounds to avoid preparing those whose predicted properties would likely make them poor drug prospects."
SEARCH FOR DIVERSITY
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