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首页> 美国卫生研究院文献>Journal of Chemical Biology >Synthesis and in silico evaluation of 1N-methyl-1S-methyl-2-nitroethylene (NMSM) derivatives against Alzheimer disease: to understand their interacting mechanism with acetylcholinesterase
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Synthesis and in silico evaluation of 1N-methyl-1S-methyl-2-nitroethylene (NMSM) derivatives against Alzheimer disease: to understand their interacting mechanism with acetylcholinesterase

机译：1N-甲基-1S-甲基-2-硝基乙烯（NMSM）衍生物对抗阿尔茨海默氏病的合成及计算机评价：了解其与乙酰胆碱酯酶的相互作用机制

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Anomalous action of human acetylcholinesterase (hAChE) in Alzheimer’s disease (AD) was restrained by various AChE inhibitors, of which the specific and potent lead candidate Donepezil is used for treating the disease AD. Besides the specificity, the observed undesirable side effects caused by Donepezil invoked the quest for new lead molecules with the increased potency and specificity for AChE. The present study elucidates the potency of six 1N-methyl-1S-methyl-2-nitroethylene (NMSM) derivatives to form a specific interaction with the peripheral anionic site and catalytic anionic subsite residues of hAChE. The NMSMs were prepared in good yield from 1,1-di(methylsulfanyl)-2-nitroethylene and primary amine (or) amino acid esters. In silico interaction analysis reveals specific and potent interactions between hAChE and selected ligand molecules. The site-specific interactions formed between these molecules also results in a conformational change in the orientation of active site residues of hAChE, which prevents them from being accessed by beta-amyloid protein (Aβ), which is a causative agent for amyloid plaque formation and acetylcholine (ACh). In silico interaction analysis between the ligand-bounded hAChE with Aß and ACh confirms this observation. The variation in the conformation of hAChE associated with the decreased ability of Aβ and ACh to access the respective functional residues of hAChE induced by the novel NMSMs favors their selection for in vivo analysis to present themselves as new members of hAChE inhibitors.
机译：人类乙酰胆碱酯酶（hAChE）在阿尔茨海默氏病（AD）中的异常作用受到多种AChE抑制剂的抑制，其中特异性强效候选候选多奈哌齐可用于治疗AD。除了特异性外，由多奈哌齐引起的不良副作用还引起了人们对新的先导分子的追求，这些新的先导分子对AChE的效力和特异性均得到提高。本研究阐明了六个1N-甲基-1S-甲基-2-硝基乙烯（NMSM）衍生物与hAChE的周围阴离子位点和催化阴离子亚位点残基形成特异性相互作用的能力。由1,1-二（甲基硫烷基）-2-硝基乙烯和伯胺（或）氨基酸酯以高收率制备NMSM。电子相互作用分析揭示了hAChE与选定配体分子之间的特异性和有效相互作用。这些分子之间形成的位点特异性相互作用还导致hAChE活性位点残基的方向发生构象变化，从而阻止它们被β-淀粉样蛋白（Aβ）访问，β-淀粉样蛋白是淀粉样蛋白斑形成的致病因子，乙酰胆碱（ACh）。在与Aß和ACh结合的配体结合的hAChE之间进行的计算机相互作用分析证实了这一观察结果。 hAChE构象的变化与由新型NMSM诱导的Aβ和ACh进入hAChE各个功能残基的能力降低有关，有利于其选择用于体内分析，以表现为hAChE抑制剂的新成员。

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