Computational method for estimating progression saturation of analog series

In lead optimization, it is difficult to estimate when an analog series might be saturated and synthesis of additional compounds would be unlikely to yield further progress. Rather than terminating a series, one often continues to generate analogs hoping to reach the final optimization goal, even if obstacles that are faced ultimately prove to be unsurmountable. Clearly, methodologies to better understand series progression and saturation are highly desirable. However, only a few approaches are currently available to monitor series progression and aid in decision making. Herein, we introduce a new computational method to assess progression saturation of an analog series by relating the properties of existing compounds to those of synthetic candidates and comparing their distributions in chemical space. The neighborhoods of analogs are analyzed and the distance relationships between existing and candidate compounds quantified. An intuitive dual scoring scheme makes it possible to characterize analog series and their degree of progression saturation.

Chemical space view of an analog series. Shown are inactive (red) and active (blue) analogs together with virtual candidate compounds (green) available to expand the series. Chemical neighborhoods of analogs are depicted in gray.