The Rise and Fall of a Scaffold: A Trend Analysis of Scaffolds in the Medicinal Chemistry Literature

Scaffolds are a core
concept in medicinal chemistry, and they can
be the focus of multiple independent development efforts over an extended
period. Thus, scaffold associated properties can vary over time, possibly
showing consistently increasing or decreasing trends. We posit that
such trends characterize the attention that the community pays to
a scaffold. In this study, we employed data from ChEMBL20 to examine
the evolution of scaffold features, such as enumerated compounds,
biological activity, and liabilities, over 17 years. Our analysis
highlights that certain properties such as enumerated compounds, but
not liabilities, show statistically significant increasing trends
for some scaffolds. We also attempt to explain why a scaffold receives
more attention over time and highlight that obvious aspects such as
synthetic feasibility do not explicitly drive attention. In summary,
trend analyses of scaffold properties could support scaffold selection
and prioritization in small molecule development projects.