One-bead, one-compound, one drug?

To identify new anti-infectives, researchers at University of California-Davis

Randall C Willis
DAVIS, Calif.—To identify new anti-infectives, researchers at University of California-Davis and Central Connecticut State University recently took a cue from the statin drugs, using one-bead one-compound combinatorial libraries to link substrate analogues to chemical moieties that enhance active-site binding. The researchers targeted a key enzyme in the shikimate pathway, which is absent in humans but critical to microbial survival.
 
As they reported in the Journal of Medicinal Chemistry, the researchers generated a bead library of amino acids and acids to a stable analogue of chorismate, the product of ADCS. They then presorted the library to eliminate autofluorescent molecules, and combined the remaining library members with fluorescently labeled ADCS, using COPAS sorting to automatically select enzyme-bound beads.
 
Of the ~2300 compounds generated, the researchers selected 15 for further analysis with ADCS and isolated one compound with a Ki of 360 µM. Further kinetics studies allowed the researchers to develop rough structure-activity guidelines for further compound development.

Randall C Willis

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