Pseudo-dynamic Combinatorial Libraries
Author | : Jeremy D. Cheeseman |
Publisher | : |
Total Pages | : 314 |
Release | : 2004 |
Genre | : |
ISBN | : |
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"Emerging methods of combinatorial chemistry involve receptor assistance to combine synthesis and screening. Binding to the receptor alters either the thermodynamics or kinetics of synthesis. Dynamic combinatorial chemistry uses reversible synthesis where binding to the receptor shifts the equilibrium to make more of the best binders. In target-accelerated synthesis, binding of the starting materials to the receptor speeds up the synthesis of the best-binding compounds. We report a new receptor-assisted method---pseudo-dynamic combinatorial chemistry---where binding to a receptor slows the destruction of the best-binding compounds. In pseudo-dynamic libraries, synthesis and destruction of library members are separate, irreversible reactions. Extending the destruction reaction amplifies binding differences similar to a kinetic resolution of enantiomers. Initial libraries of two to eight dipeptides, some containing an aryl sulfonamide moiety that binds to carbonic anhydrase, showed that a ratio of >100:1 of the best binding dipeptide over the next best was possible. These experiments also suggested that the selectivity is related to the number of compounds in a library, with more library members producing higher selectivity (a highly desirable result opposite that seen in traditional dynamic libraries). Expansion of these libraries to include compounds containing sulfonamides, aryl sulfonamides, sulfamates and hydroxamic acids further support postulations as to the origins of the high selectivity of these systems, and take the number of compounds screened by a pseudo-dynamic library closer to practical levels for drug discovery." --