The π–π stacking of tanshinone I and isotanshinone I with phenylalanine: The effects of isomerization, complexation and environment

Abstract

The misfolding and aggregation of amyloid-[Formula: see text] (A[Formula: see text] peptides into amyloid fibrils is regarded as one of the possible causes of Alzheimer’s disease (AD). Aromatic interactions (i.e. [Formula: see text]–[Formula: see text] interactions) between tanshinone drugs extracted from Chinese herb Salvia Miltiorrhiza (SM) and aromatic residues of A[Formula: see text] peptides have been shown to prevent further growth of amyloid aggregates. In this work, the effects of isomerization, complexation and polarity of environment on the strength of [Formula: see text]–[Formula: see text] stacking interactions of tanshinone I (TS1) and isotanshinone I (IS1), as the two diterpenoid quinones in the SM herb, and their complexes with Mg[Formula: see text] cation, IS1-Mg[Formula: see text] and TS1-Mg[Formula: see text], with phenylalanine (PHE), as an aromatic amino acid in A[Formula: see text] structure have been investigated using the quantum mechanical calculations in the gas-phase, ether, acetone, DMSO, and water solvent. Molecular electrostatic potential (MEP), which are used to predict the nucleophile active sites, electron densities calculated at the bond critical points ([Formula: see text] and ring critical points ([Formula: see text] by the atoms in molecules (AIM) method and the donor–acceptor interaction energies ([Formula: see text] calculated using the natural bond orbital (NBO) method were used to investigate the interplay between [Formula: see text]–[Formula: see text] stacking and complexation. The results show that the IS1/TS1-Mg[Formula: see text] compounds have a more protective role compared to TS1/IS1-Mg[Formula: see text] compounds due to the stronger interaction with PHE of A[Formula: see text] in antiaggregation for further development of A[Formula: see text] inhibitors to prevent and disaggregate amyloid formation. Complexation with Mg[Formula: see text] increases the interaction diterpenoid drugs with PHE and makes notable changes in structural and electronic properties of diterpenoids. Also, the interactions between diterpenoid and PHE in less polar environment are more than other environments. Low-polarity environments have the best mimics of the A[Formula: see text] binding site.