乙酰胆碱酯酶和β -分泌酶抑制剂:潜在的多靶点抗阿尔茨海默病药物的计算机研究。

Q3 Psychology
Daniel Castro da Costa, Hueldem Ronam Cristo Teixeira, Raí Campos Silva, Isaque Antonio Galindo Francischini, Carlos Henrique Tomich de Paula da Silva, Lorane Izabel da Silva Hage-Melim
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引用次数: 0

摘要

背景:阿尔茨海默病是一种具有多因素特征的进行性神经退行性疾病。这种疾病遵循自然衰老过程,主要影响65岁以上的人。药物治疗目前对抗的是与认知功能相关的症状。一些目标已经开始引起科学界的兴趣,以开发具有更好的药代动力学和更低的毒性参数的新候选药物。目的:设计新的乙酰胆碱酯酶/β-分泌酶(AChE/BACE1)多靶点抑制剂候选药物。方法:从文献中筛选出17种具有抗胆碱酯酶活性的天然产物和1种具有抑制BACE1活性的合成分子。随后进行分子对接研究,推导药效谱,预测药代动力学和毒理学特性。最后,设计了混合动力样机。结果:所选分子均与靶酶表现出相互作用。从与乙酰胆碱酯酶相互作用的分子中衍生出的药效模式产生了3个药效区域:芳香环、电子受体区域和疏水区域。这些分子显示出良好的药代动力学和毒理学结果,没有显示出致突变性和/或致癌性的警告。杂交后得到3个杂化分子,对两个靶点均有抑制活性。结论:药物化学领域的研究正朝着发现新的候选药物的方向发展,为阿尔茨海默病患者带来更好的生活质量。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
In silico Study of Acetylcholinesterase and Beta-secretase Inhibitors: Potential Multitarget Anti-Alzheimer's Agents.

Background: Alzheimer's disease is a progressive neurodegenerative process with multifactorial characteristics. This disease follows the natural aging process, affecting mainly people over 65 years. Pharmacotherapeutic treatment currently combats symptoms related to cognitive function. Several targets have begun to attract the interest of the scientific community to develop new drug candidates which have better pharmacokinetic and lower toxicity parameters.

Objective: The present study aims to design new candidates for acetylcholinesterase/β-secretase (AChE/BACE1) multitarget inhibitor drugs.

Methods: 17 natural products were selected from the literature with anticholinesterase activity and 1 synthetic molecule with inhibitory activity for BACE1. Subsequently, the molecular docking study was performed, followed by the derivation of the pharmacophoric pattern and prediction of pharmacokinetic and toxicological properties. Finally, the hybrid prototype was designed.

Results: All selected molecules showed interactions with their respective target enzymes. Derivation of the pharmacophoric pattern from molecules that interacted with the AChE enzyme resulted in 3 pharmacophoric regions: an aromatic ring, an electron-acceptor region and a hydrophobic region. The molecules showed good pharmacokinetic and toxicological results, showing no warnings of mutagenicity and/or carcinogenicity. After the hybridization process, three hybrid molecules were obtained, which showed inhibitory activity for both targets.

Conclusion: It is concluded that research in the field of medicinal chemistry is advancing towards the discovery of new drug candidates that bring a better quality of life to patients with AD.

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来源期刊
Central nervous system agents in medicinal chemistry
Central nervous system agents in medicinal chemistry Psychology-Neuropsychology and Physiological Psychology
CiteScore
2.10
自引率
0.00%
发文量
21
期刊介绍: Central Nervous System Agents in Medicinal Chemistry aims to cover all the latest and outstanding developments in medicinal chemistry and rational drug design for the discovery of new central nervous system agents. Containing a series of timely in-depth reviews written by leaders in the field covering a range of current topics, Central Nervous System Agents in Medicinal Chemistry is an essential journal for every medicinal chemist who wishes to be kept informed and up-to-date with the latest and most important developments in the field.
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