Molecular docking and molecular dynamicsof semi-synthetic piperidine alkaloids as acetylcholinesterase inhibitors

Abstract

A mistura dos derivados semissintéticos cloridrato da (–)-3-O-acetil-cassina e cloridrato da (–)-3-O-acetil-espectalina, preparada a partir da mistura dos alcalóides (–)-cassina e (–)-espectalina (4:1) obtida de Senna spectabilis, é um potente inibidor da acetilcolinesterase (AChE), assim justificando mais estudos moleculares. Neste sentido, estudos de docking e dinâmica moleculares foram conduzidos neste trabalho com o objetivo de adquirir uma compreensão mais profunda de todos os aspectos estruturais das moléculas cloridratos da (–)-3-O-acetil-cassina e (–)-3-O-acetil-espectalina, as quais diferem em seus potenciais inibidores de AChE. Os dois derivados em estudo apresentaram diversas interações com o sítio periférico aniônico dentro da cavidade catalítica de AChE de Torpedo californica. Entretanto, somente o composto majoritário (–)-3-O-acetil-cassina mostrou interação com a tríade catalítica de maneira significativa. As simulações de dinâmica molecular utilizando água como solvente foram importantes para compreender as interações hipotéticas entre cloridratos da (–)-3-O-acetil-cassina e (–)-3-O-acetil-espectalina com AChE. Os dados obtidos indicam que o composto (–)-3-O-acetil-cassina é o inibidor da enzima mais potente possivelmente devido às suas interações favoráveis com a proteína, com menor custo de dessolvatação. Estes resultados sugerem que o tamanho da cadeia lateral influencia no potencial inibitório das moléculas avaliadas e podem representar o ponto de partida para o desenvolvimento de novos derivados de (–)-3-O-acetil-cassina, objetivando a descoberta de inibidores de AChE mais eficazes.

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.