Abstract: One aspect of the present invention relates to methods of identifying cortisone response signature gene sets and methods of using the identified gene sets to identify compounds that modulate HSD1 activity. In some embodiments, methods are provided to use cortisone response gene sets to estimate the HSD1 activity. Another aspect of the present inventive relates to methods for identification of off-target signature gene sets that can be used to estimate HSD1 compound induced off-target activity and methods for classification of compounds that modulate HSD1 activity. Another aspect of the present invention relates to cell lines that over-expresses HSD1 and methods of use thereof. Additional embodiments of the of the invention are described in the specification provided herein. The contents of this ABSTRACT are not intended to in anyway limit the scope of the invention claimed herein.