Exploring Chemical Diversity: Towards Rational Synthesis and Analysis of Large Ordered Libraries
Neal Woodbury
Department of Chemistry and Biochemistry
Arizona State University
A variety of methods have been developed for the exploration of
chemical space with reference to a particular function. In the
pharmaceutical industry, combinatorial chemistry has been used to
generate moderately large (105 to 106) libraries of compounds that can
then be tested either as mixtures or individually. Biochemical
methods such as phage display, SELEX and mRNA display have made it
possible to screen much larger libraries (up to about 1013) of
biopolymers for members with optimal binding and in some cases
catalysis. Both approaches have advantages. The combinatorial
chemical libraries are small enough to allow testing of individual
chemicals, providing a complete correlation between structure and
function for a particular library. However, it is time consuming to
create and analyze these libraries making it difficult to perform
iterative improvement of molecular function in this way. The
biochemical libraries allow the exploration of much more structural
space, and they can be readily iterated to improve function in
multiple rounds of mutagenesis and selection, but generally they
provide only functional information about the molecules that emerge
from the particular selection method used, rather than correlated
structure/function relationships in the whole library. We have been
developing technology pioneered by the DNA chip industry to explore
ordered libraries of heteropolymers on surfaces. This allows the use
of moderate sized libraries (105 or more) and provides
structure/function information for all elements of the library. It
also provides a rapid means of creating new libraries based on the
results of previous libraries for iterative improvement of function.
Our initial work has been done using DNA chips themselves and looking
at the structure function properties of libraries of DNA aptamers. In
addition, we have been developing similar high throughput synthetic
methods for creating moderate sized libraries of peptides and other
amide-linked heteropolymers. One application of this work has been
the selection of ligands for assembly into synthetic antibodies and
this work will be described. Computationally, challenges exist in
developing algorithms both for creating the initial libraries,
analyzing the structure function correlations that come out of these
screens, and then using this information to create new libraries that
facilitate the discovery of molecules with desired function.
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