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Scripps Research scientists create new way to screen libraries of 10 million or more compounds
Date:2/1/2010

day."

Ligands are compounds that attach to proteins and alter their expression, potentially affecting a particular biomolecular activity, say, a protein pathway involved in a disease.

The new method displays millions of compounds on the surface of resin-based beads, each type of compound on a different bead. The hits are culled from the beads using a unique magnetic signature and then transferred to a microarray formatglass slides or silicon chips that can hold large numbers of compounds on their surface. The microarray format allows quantitative comparison of binding affinity that can be carried out without the need for tedious re-synthesis of many different compounds.

In the study, the team used mixed peptide/peptoid librariespeptides make up proteins; peptoids are molecules closely related to, but more stable than peptides, making them more convenient for testingbut the method could be applied to any class of compound, according to Kodadek.

Changing the Paradigm

The Kodadek group's method combines several different technical advances to enable this convenient and efficient screening.

These days, most active molecules are discovered through screening of two basic types. There are functional screens, in which small molecules are introduced into the wells of microtiter platesflat plates with multiple wells that can reach as high as 9,600and tested individually for their ability to alter the activity of an enzyme. Alternatively, there are binding assays, an approach first developed for bead-displayed peptide libraries, where each bead displays many copies of a single molecule.

"Our new method for screening synthetic libraries and characterizing the resultant hits combines many of the features of bead library screening and microarray-based analysis in a seamless fashion," Kodadek said. "The new technique uses several million beads, each of which displays a unique ligandtheoretically as many as 64
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Contact: Keith McKeown
kmckeown@scripps.edu
858-784-8134
Scripps Research Institute
Source:Eurekalert

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