Molecular docking and molecular dynamic studies of semi-synthetic piperidine alkaloids as acetylcholinesterase inhibitors

Amanda Danuello,Nelilma C Romeiro,Claudio Viegas Jr,Newton G Castro,Carlos A M Fraga,Hugo Verli,Eliezer J Barreiro,Guilherme M Giesel,Vanderlan S Bolzani,Marcos Pivatto

doi:10.1590/s0103-50532012000100023

Abstract

The mixture of semi-synthetic derivatives (-)-3-O-acetyl-cassine hydrochloride and (-)-3-O-acetyl-spectaline hydrochloride, prepared from the mixture of natural alkaloids (-)-cassine and (-)-spectaline (4:1) isolated from Senna spectabilis, has been shown to be a potent acetylcholinesterase (AChE) inhibitor, thereby prompting further molecular studies. In this sense, docking and dynamic molecular studies were carried out in this work, aiming to acquire a deeper understanding about all the structural aspects of molecules (-)-3-O-acetyl-cassine and (-)-3-O-acetyl-spectaline hydrochlorides, which differ with respect to their AChE inhibitory potentials. Both molecules establish important interactions with the peripheral anionic site within the catalytic gorge of Torpedo californica AChE. However, only the major compound (-)-3-O-acetyl-cassine hydrochloride significantly interacts with the catalytic triad. Explicit-solvent molecular dynamic simulations were conducted in order to gain better understanding about the hypothetical interactions taking place between the semi-synthetic alkaloid molecules (-)-3-O-acetyl-cassine and (-)-3-O-acetyl-spectaline hydrochlorides and AChE. The data obtained in this study indicated that (-)-3-O-acetyl-cassine hydrochloride is the most potent inhibitor of AChE possibly due to the favorable interactions of this molecule with the target protein, with lower desolvation cost. These results suggested that the size of the side chain has an effect on the inhibitory potential of the evaluated molecules and may represent the starting point for the development of new derivatives of (-)-3-O-acetyl-cassine hydrochloride, with a view to the discovery of new effective AChE inhibitors.

Highlights

Alzheimer’s disease (AD) is a late-onset neurodegenerative pathology that affects the memory, motor coordination, and cognition in a progressive, and eventually lethal, manner.[1,2,3] It has been postulated that at least some of the cognitive impairment experienced by AD patients results from deficient acetylcholine levels and consequent reduction in cholinergic neurotransmission
The data obtained in this study indicated that (–)-3-O-acetyl-cassine hydrochloride is the most potent inhibitor of AChE possibly due to the favorable interactions of this molecule with the target protein, with lower desolvation cost
These results suggested that the size of the side chain has an effect on the inhibitory potential of the evaluated molecules and may represent the starting point for the development of new derivatives of (–)-3-O-acetyl-cassine hydrochloride, with a view to the discovery of new effective AChE inhibitors

Summary

Introduction

Alzheimer’s disease (AD) is a late-onset neurodegenerative pathology that affects the memory, motor coordination, and cognition in a progressive, and eventually lethal, manner.[1,2,3] It has been postulated that at least some of the cognitive impairment experienced by AD patients results from deficient acetylcholine levels and consequent reduction in cholinergic neurotransmission. Only five drugs have received approval in the USA and Europe for therapeutic use in AD, namely tacrine (1; CognexTM),[4] donepezil (2; AriceptTM),[5] rivastigmine (3; ExcelonTM),[6] galantamine (4; ReminylTM)[7] and memantine (5; EbixaTM)[8] (Figure 1). All of these compounds are acetylcholinesterase inhibitors (AChEIs),[4,5,6,7] with the single exception of 5, which acts by blocking the N-methyl-D-aspartate (NMDA) glutamate receptors. That inhibition of acetylcholinesterase remains an important therapeutic strategy to the palliate cognitive deficit in AD

Objectives

Methods

Findings

Conclusion