Amphiphilic cyclodextrins: Dimerization and diazepam binding explored by molecular dynamics simulations

Amphiphilic cyclodextrins spontaneously aggregate to form different supramolecular assemblies with potential applications in drug release. Herein, we employ extended molecular dynamics simulations in order to characterize the structure and dynamics in explicit solvent of several amphiphilic derivatives of the beta-cyclodextrin (beta-CD) molecule, with aliphatic chains ester-bound to the wide rim of the hydrophobic cavity. We also study the binding properties considering a typical guest (diazepam) and the dimerization of these macrocyclic systems, assessing the relative stability of the complexes by means of end-point free energy methods. Different lengths (C-4, C-10, and C-14 atoms) are considered for the alkyl side chains included in the amphiphilic beta-CD-C-n molecules. According to the simulations, the length of these C-n moieties determines the complexing and aggregation capabilities of the beta-CD-C-n systems. Compared to the native beta-CD, the alkyl side chains in the beta-CD-C-n molecules destabilize the inclusion complexes with diazepam and hinder the access of guest molecules to the hydrophobic cavity. In turn, dimerization is favored in the largest amphiphilic derivatives associated to the hydrophobic interaction between the C-n fragments. (C) 2022 The Authors. Published by Elsevier B.V.

Automated summary

Amphiphilic cyclodextrins can spontaneously form supramolecular assemblies with potential applications in drug release. Molecular dynamics simulations were used to characterize the structure, dynamics, binding properties, and aggregation capabilities of several amphiphilic derivatives of beta-cyclodextrin. The length of alkyl side chains in these derivatives plays a crucial role in determining their complexing abilities and aggregation tendencies.