Applications of Systematic Molecular Scaffold Enumeration to Enrich Structure–Activity Relationship Information

Establishing
structure–activity relationships (SARs) in
hit identification during early stage drug discovery is important
in accelerating hit confirmation and expansion. We describe the development
of EnCore, a systematic molecular scaffold enumeration
protocol using single atom mutations, to enhance the application of
objective scaffold definitions and to enrich SAR information from
analysis of high-throughput screening output. A list of 43 literature
medicinal chemistry compound series, each containing a minimum of
100 compounds, published in the Journal of Medicinal Chemistry was collated to validate the protocol. Analysis using the top representative
Level 1 scaffolds this list of literature compound series demonstrated
that EnCore could mimic the scaffold exploration
conducted when establishing SAR. When EnCore was
applied to analyze an HTS library containing over 200 000 compounds,
we observed that over 70% of the molecular scaffolds matched extant
scaffolds within the library after enumeration. In particular, over
60% of the singleton scaffolds with only one representative compound
were found to have structurally related compounds after enumeration.
These results illustrate the potential of EnCore to
enrich SAR information. A case study using literature cyclooxygenase-2
inhibitors further demonstrates the advantage of EnCore application in establishing SAR from structurally related scaffolds. EnCore complements literature enumeration methods in enabling
changes to the physicochemical properties of molecular scaffolds and
structural modifications to aliphatic rings and linkers. The enumerated
scaffold clusters generated would constitute a comprehensive collection
of scaffolds for scaffold morphing and hopping.