QSAR studies for prediction of cross-β sheet aggregate binding affinity and selectivity.

Protein aggregates that accumulate in neurodegenerative diseases are important targets of radiotracer discovery efforts. Although multiple scaffold classes have been reported to bind cross-β sheet structure, their mechanism of binding and their ability to interact selectively with aggregates of varying protein composition are not well understood. Here we take a ligand-based quantitative structure-activity relationship approach to identify descriptors of binding affinity and selectivity for a series of 50 closely related benzothiazole derivatives reported to displace Thioflavin T fluorescent probe from synthetic aggregates composed of β-amyloid peptide and insulin. Using a two-step workflow involving both partial least squares and multiple linear regression methods, compound polarizability and hydrophobicity were identified as tunable mediators of binding selectivity. The correlations also revealed how polarizability could be modulated in neutral compounds having push-pull character. These data suggest that the relative affinity of small molecules for binding sites exposed on aggregate surfaces can be modulated by simple chemical design considerations that are compatible with multiple scaffolds.