Fragment-Based Discovery and Optimization of Enzyme Inhibitors by Docking of Commercial Chemical Space

Fragment-based lead
discovery has emerged as a leading drug development
strategy for novel therapeutic targets. Although fragment-based drug
discovery benefits immensely from access to atomic-resolution information,
structure-based virtual screening has rarely been used to drive fragment
discovery and optimization. Here, molecular docking of 0.3 million
fragments to a crystal structure of cancer target MTH1 was performed.
Twenty-two predicted fragment ligands, for which analogs could be
acquired commercially, were experimentally evaluated. Five fragments
inhibited MTH1 with IC50 values ranging from 6 to 79 μM.
Structure-based optimization guided by predicted binding modes and
analogs from commercial chemical libraries yielded nanomolar inhibitors.
Subsequently solved crystal structures confirmed binding modes predicted
by docking for three scaffolds. Structure-guided exploration of commercial
chemical space using molecular docking gives access to fragment libraries
that are several orders of magnitude larger than those screened experimentally
and can enable efficient optimization of hits to potent leads.