Ligand polarizability contributes to tau fibril binding affinity

Structural Determinants of Tau Aggregation Inhibitor Potency

“…However, this approach requires high-micromolar to low-millimolar concentrations of ligand, and it is not clear that natively unfolded protein structures could support such interactions at the low protein concentrations used to demonstrate aggregation inhibition. Using thioflavin dye displacement as another secondary assay, direct interaction between phenothiazines, cyanines, and arylmethines with mature Tau fibrils has been reported as well (14). Although such binding can be high affinity, it is difficult to rationalize aggregation inhibitory activity in terms of this target alone.…”

“…10). Because we previously reported that polarizability is a descriptor of high affinity binding to a cross-␤-sheet structure (14), it is tempting to propose that the target has ␤-sheet character. However, ␣-helices also can present appropriate surfaces for binding -delocalized ligands (70), and these too have been proposed to form in conjunction with anionic surfaces (71).…”

“…Polarizability is an electronic property that describes how easily electron density can shift about a molecule when exposed to an external electric field, such as an adjacent dipole or ion. For planar molecules, high polarizability can support strong van der Waals interactions with flat surfaces exposed on binding partners (14). In contrast, reports of SAR analysis within rhodanine and phenothiazine families have focused on sterics rather than chemical descriptors of graded biological potency (15,16).…”

“…The pruned descriptor set was then augmented with clogP and topological polar surface area values were calculated using the Molinspiration Property Calculation Service, and with polarizability (␣) values calculated at the quantum level using density functional theory methods implemented in Gaussian 09 (G09) (43). We described these methods in detail previously (14,37). Quantum calculations were performed in implicit solvent using the density field theory functional B3LYP and the 6 -311ϩϩG(d,p) basis set to more accurately model the photophysical properties of dye molecules (44).…”

“…The phenothiazines included the established aggregation inhibitor 10 (methylene blue) and four analogs (11)(12)(13)(14) that differed solely in the strengths of the electron donor/acceptor groups flanking the phenothiazine nucleus ( Table 2). As a result, this series varied over relatively narrow ranges of molecular weight and hydrophobicity (Table 2).…”