Dam. Konings et al., DECONVOLUTION OF COMBINATORIAL LIBRARIES FOR DRUG DISCOVERY - THEORETICAL COMPARISON OF POOLING STRATEGIES, Journal of medicinal chemistry, 39(14), 1996, pp. 2710-2719
Synthesis and testing of mixtures of compounds in a combinatorial libr
ary allow much greater throughput than synthesis and testing of indivi
dual compounds. When mixtures of compounds are screened, however, the
possibility exists that the most active compound will not be identifie
d. The specific strategies employed for pooling and deconvolution will
affect the likelihood of success. We have used a nucleic acid hybridi
zation example to develop a theoretical model of library deconvolution
for a library of more than 250 000 compounds. This model was used to
compare various strategies for pooling and deconvolution. Simulations
were performed in the absence and presence of experimental error. We f
ound iterative deconvolution to be most reliable when active molecules
were assigned to the same subset in early rounds. Reliability was red
uced only slightly when active molecules were assigned randomly to all
subsets. Iterative deconvolution with as many as 65 536 compounds per
subset did not drastically reduce the reliability compared to one-at-
a-time testing. Pooling strategies compared using this theoretical mod
el are compared experimentally in an accompanying paper.