HTS assay design and follow-up strategy.  Development and implementation of protocols and methods that enable the detection of biological activities and biomolecular interactions.  Examples include systems that measure the catalytic activity from purified enzymes, reconstituted complexes, cellular extracts, or phenotypes of intact cells.  An additional element we consider is the integration of the primary HTS assay with subsequent or parallel assays that further characterize or validate the putative activity/mechanism of active library compounds. 

Process efficiency and scope expansion.  Advance paradigms for chemical library screening, from screening methods (e.g. qHTS), to library composition, usage, handling and QC, to the configuration of robotics systems and the integration of compound and reagent delivery devices, and detector hardware, to the analysis methods that assist in the processing and interpretation of HTS data.  Such methods can find use throughout chemical biology, and the continual integration of experimental methods into the HT realm will greatly expand the boundaries of hypothesis-driven research. 

Applying technology to chemical biology. The third area focuses on the technological interface that bridges chemistry with biology in process like HTS.  For example, to fully appreciate the nature of the molecules that influence the functioning of a cellular signaling pathway, one must understand the impact they have on the technology employed to measure that pathway.  Recently we have been studying the effects chemical libraries can have on reporter genes commonly used as a surrogate measure of cellular activity or a stimulus-mediated response.  Here we observe that a complex, but decipherable, “pharmacology” emerges from the direct inhibition of the enzymatic activity of reporter genes used to “read” the activity of cellular signaling events.  We find that considerations of both basic enzymology and cellular biology are critical to interpretation of the data based on reporter gene assays.