Inhibition of insulin amyloid fibrillization by glyco-acridines: an in vitro and in silico study

Abstract

The formation of insulin amyloid fibrils leads to accumulation of protein aggregates at the sites of insulin injection and interferes with insulin delivery for treatment of diabetes. We investigated the ability of small molecules, aromatic glyco-acridine derivatives, to prevent insulin fibrillization. Fluorescence spectroscopy and atomic force microscopy have shown that glyco-acridines interfere with insulin aggregation and that their inhibitory activity depends on their structure. The binding free energies, estimated by all-atom molecular dynamics simulations, indicate that the non-polar interaction is the key factor controlling the binding affinity of glyco-acridine derivatives to insulin. We introduced, for the first time, geometrical descriptors that allowed us to distinguish the binding affinities of stereo-isomers. The binding free energies correlate with the distance between the planes of the acridine tricyclic core and the side parts in the unbound and bound states. In addition, the aromatic part of glyco-acridines is important for directing the ligand–dimer insulin interaction. Our findings may provide a basis for the development of new small moleculeinhibitors for the treatment of amyloid-related diseases.