Fragment merging
is a promising approach to progressing
fragments
directly to on-scale potency: each designed compound incorporates
the structural motifs of overlapping fragments in a way that ensures
compounds recapitulate multiple high-quality interactions. Searching
commercial catalogues provides one useful way to quickly and cheaply
identify such merges and circumvents the challenge of synthetic accessibility,
provided they can be readily identified. Here, we demonstrate that
the Fragment Network, a graph database that provides a novel way to
explore the chemical space surrounding fragment hits, is well-suited
to this challenge. We use an iteration of the database containing
>120 million catalogue compounds to find fragment merges for four
crystallographic screening campaigns and contrast the results with
a traditional fingerprint-based similarity search. The two approaches
identify complementary sets of merges that recapitulate the observed
fragment–protein interactions but lie in different regions
of chemical space. We further show our methodology is an effective
route to achieving on-scale potency by retrospective analyses for
two different targets; in analyses of public COVID Moonshot andMycobacterium tuberculosisEthR inhibitors, potential
inhibitors with micromolar IC50values were identified.
This work demonstrates the use of the Fragment Network to increase
the yield of fragment merges beyond that of a classical catalogue
search.