Scaffold-Focused Virtual Screening: Prospective Application
to the Discovery of TTK Inhibitors
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Abstract
We describe and apply a scaffold-focused virtual screen based upon
scaffold trees to the mitotic kinase TTK (MPS1). Using level 1 of
the scaffold tree, we perform both 2D and 3D similarity searches between
a query scaffold and a level 1 scaffold library derived from a 2 million
compound library; 98 compounds from 27 unique top-ranked level 1 scaffolds
are selected for biochemical screening. We show that this scaffold-focused
virtual screen prospectively identifies eight confirmed active compounds
that are structurally differentiated from the query compound. In comparison,
100 compounds were selected for biochemical screening using a virtual
screen based upon whole molecule similarity resulting in 12 confirmed
active compounds that are structurally similar to the query compound.
We elucidated the binding mode for four of the eight confirmed scaffold
hops to TTK by determining their protein–ligand crystal structures;
each represents a ligand-efficient scaffold for inhibitor design