Probing the ATP-Binding Pocket of Protein Kinase DYRK1A with Benzothiazole Fragment Molecules

DYRK1A has emerged
as a potential target for therapies of Alzheimer’s
disease using small molecules. On the basis of the observation of
selective DYRK1A inhibition by firefly d-luciferin, we have
explored static and dynamic structural properties of fragment sized
variants of the benzothiazole scaffold with respect to DYRK1A using
X-ray crystallography and NMR techniques. The compounds have excellent
ligand efficiencies and show a remarkable diversity of binding modes
in dynamic equilibrium. Binding geometries are determined in part
by interactions often considered “weak”, including “orthogonal
multipolar” types represented by, for example, F–CO,
sulfur–aromatic, and halogen–aromatic interactions,
together with hydrogen bonds that are modulated by variation of electron
withdrawing groups. These studies show how the benzothiazole scaffold
is highly promising for the development of therapeutic DYRK1A inhibitors.
In addition, the subtleties of the binding interactions, including
dynamics, show how full structural studies are required to fully interpret
the essential physical determinants of binding.