Biophysical screening was employed to identify potential binders to kynurenine amino transferase II (KAT II) from a collection of low molecular weight chemical fragments. Lead exploration was accomplished using parallel synthesis, guided by data from X-ray crystallography, biophysical measurements and, ultimately, an inhibition assay. X-ray data drove the structure-based design and also revealed a unexpected change in binding pose. These efforts led to the successful development of weak biophysical hit, with no measurable KAT II inhibition, into a viable chemical series containing a lead that shows sub-micromolar inhibition of the enzyme.

Fragment-based discovery of KAT II inhibitors via high-throughput chemistry

256th National Meeting (2018)

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