Structural basis of fullerene derivatives as novel potent inhibitors of protein acetylcholinesterase without catalytic active site interaction: insight into the inhibitory mechanism through molecular modeling studies

Abstract

Acetylcholinesterase (AChE) is an important kind of esterase that plays a key biological role in the central and peripheral nervous systems. Recent research has demonstrated that some fullerene derivatives serve as a new nanoscale class of potent inhibitors of AChE, but the specific inhibition mechanism remains unclear. In the present article, several molecular modeling methods, such as molecular docking, molecular dynamics simulations and molecular mechanics/generalized Born surface area calculations, were used for the investigation of the binding mode and inhibition mechanism of fullerene inhibitions for AChE. Results revealed that fullerene inhibitors block the entrance of substrates by binding with the peripheral anionic site (PAS) region. Thus, fullerene derivatives might mainly serve as competitive inhibitors. The interactions of a fullerene backbone with AChE are at the same level in different single side chain systems and seem to be related to the length or aromaticity of the side chain. The inhibitor with multihydroxyl side chains shows an obviously large electrostatic interaction as it forms additional hydrogen bonds with AChE. Moreover, fullerene derivatives might exhibit noncompetitive inhibition partly by affecting some secondary structures around them. Thus, the destructions of these secondary structures can lead to conformational changes in some important regions, such as the catalytic triad and acyl pocket. The investigation is of great importance to the discovery of good fullerene inhibitors.

Communicated by Ramaswamy H. Sarma

Keywords:

• Acetylcholinesterase
• inhibitor
• fullerene derivative
• molecular simulation

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

This work was financially supported by the Science and Technology Research Project in 13th Five-Year Plan Period of Education Department of Jilin Province [Grants 2016406 and 2016408] and the Industrial Technology Research and Development Projects of Jilin Province Development and Reform Commission [Grant 2014Y081]; the National Natural Science Foundation of China [Grant 31770996]; the Science and Technology Enterprise Technology Innovation Fund by Jiangsu Province Science and Technology Department [Grant BC2015065]; Key Project of Xuzhou Mapeptide Biotechnology Co., Ltd. [Grants 2016220101000815 and 3R2173651449].