Systematic Study of Heteroarene Stacking Using a Congeneric Set of Molecular Glues for Procaspase‑6

Heteroaromatic stacking interactions are important in
drug binding,
supramolecular chemistry, and materials science, making protein–ligand
model systems of these interactions of considerable interest. Here
we studied 30 congeneric ligands that each present a distinct heteroarene
for stacking between tyrosine residues at the dimer interface of procaspase-6.
Complex X-ray crystal structures of 10 analogs showed that stacking
geometries were well conserved, while high-accuracy computations showed
that heteroarene stacking energy was well correlated with predicted
overall ligand binding energies. Empirically determined KD values in this system thus provide a useful measure
of heteroarene stacking with tyrosine. Stacking energies are discussed
in the context of torsional strain, the number and positioning of
heteroatoms, tautomeric state, and coaxial orientation of heteroarene
in the stack. Overall, this study provides an extensive data set of
empirical and high-level computed binding energies in a versatile
new protein–ligand system amenable to studies of other intermolecular
interactions.