Structural Distortion of β-Cyclodextrin Plays a Key Role in the pH-dependent Host–Guest Chemistry with Doxorubicin, Evident by the Electrochemical and Molecular Dynamics Approach

Abstract

β-Cyclodextrin (β-CD) is the potential drug carrier to deliver antitumor drugs like doxorubicin (DOX). However, the mechanism for the inclusion complex formation is still unclear and needs to be explored. This study investigated the effect of pH on the inclusion of DOX into thiolated β-CD (β-CD-SH) by electrochemical and molecular dynamics (MD) simulation. The electrochemical study shows a clear difference at different pH values. The redox peak due to the DOX is strongly influenced by pH. At neutral pH, the peak intensity decreases with time, while slight variation is observed at acidic and basic pH, depicting the association of DOX to the β-CD-SH cavity at neutral pH. Also, due to the association, the charge transfer resistance variation increased with time at neutral pH and decreased at basic and acidic pH. The electrochemical study was further supported by MD simulation, suggesting that the cyclodextrin (CD) ring gets slightly elongated due to the flipping of glucose units, specifically at neutral pH leading to a strong association. Also, another significant result observed that the DOX forms an inclusion complex with β-CD-SH in quinol conformation, not in quinone. Briefly, the study provides the necessary molecular binding information for designing an effective β-CD-based targeted drug delivery system.

An enantioselective study of β‐cyclodextrin and ionic liquid‐β‐cyclodextrin towards propranolol enantiomers by molecular dynamic simulations

“…The center of the box was fixed at the center of β‐CD. It is acknowledged that the glucose rings in β‐CD may undergo flipping 41,42 and influence the inclusion behavior. However in this study, the β‐CD structure was rigidly fixed to investigate the most stable state and isolate the key interactions with propranolol.…”