Innovative approaches in acetylcholinesterase inhibition: a pathway to effective Alzheimer's disease treatment.

IF 3.9 2区化学 Q2 CHEMISTRY, APPLIED

Molecular Diversity Pub Date : 2025-03-24 DOI:10.1007/s11030-025-11170-1

Pinky Arora, Swati, Supriya Rani, Sumeet Jha, Sneha Gupta, Shubham Kumar

{"title":"Innovative approaches in acetylcholinesterase inhibition: a pathway to effective Alzheimer's disease treatment.","authors":"Pinky Arora, Swati, Supriya Rani, Sumeet Jha, Sneha Gupta, Shubham Kumar","doi":"10.1007/s11030-025-11170-1","DOIUrl":null,"url":null,"abstract":"<p><p>Acetylcholinesterase inhibitors (AChEIs) are essential in the treatment of neurodegenerative disorders like Alzheimer's disease, as they prevent the breakdown of acetylcholine, thereby enhancing cognitive function. This review provides a comprehensive analysis of the structural motifs and mechanisms governing AChEI pharmacological activity, with a focus on medicinal chemistry strategies to enhance potency, selectivity, and pharmacokinetic properties. Beginning with the physiological role of acetylcholinesterase in neurological disorders, the review explores the historical evolution of AChEIs and highlights key structural interactions with catalytic, peripheral anionic, and allosteric binding sites. Advances in computational modeling, virtual screening, and structure-based drug design are discussed, alongside emerging approaches, such as multi-target-directed ligands and prodrugs. Additionally, the significance of natural products and drug repurposing in identifying novel AChEI scaffolds is emphasized, contributing to chemical diversity and innovation in drug discovery. By integrating computational tools, expansive chemical libraries, and innovative design strategies, this review identifies promising directions for developing effective AChEIs. These advancements hold great potential in addressing the multifaceted nature of neurodegenerative diseases and improving therapeutic interventions.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":3.9000,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Molecular Diversity","FirstCategoryId":"92","ListUrlMain":"https://doi.org/10.1007/s11030-025-11170-1","RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"CHEMISTRY, APPLIED","Score":null,"Total":0}

引用次数: 0

Abstract

Acetylcholinesterase inhibitors (AChEIs) are essential in the treatment of neurodegenerative disorders like Alzheimer's disease, as they prevent the breakdown of acetylcholine, thereby enhancing cognitive function. This review provides a comprehensive analysis of the structural motifs and mechanisms governing AChEI pharmacological activity, with a focus on medicinal chemistry strategies to enhance potency, selectivity, and pharmacokinetic properties. Beginning with the physiological role of acetylcholinesterase in neurological disorders, the review explores the historical evolution of AChEIs and highlights key structural interactions with catalytic, peripheral anionic, and allosteric binding sites. Advances in computational modeling, virtual screening, and structure-based drug design are discussed, alongside emerging approaches, such as multi-target-directed ligands and prodrugs. Additionally, the significance of natural products and drug repurposing in identifying novel AChEI scaffolds is emphasized, contributing to chemical diversity and innovation in drug discovery. By integrating computational tools, expansive chemical libraries, and innovative design strategies, this review identifies promising directions for developing effective AChEIs. These advancements hold great potential in addressing the multifaceted nature of neurodegenerative diseases and improving therapeutic interventions.

查看原文本刊更多论文

乙酰胆碱酯酶抑制的创新方法：有效治疗阿尔茨海默病的途径。

乙酰胆碱酯酶抑制剂（AChEIs）在治疗阿尔茨海默病等神经退行性疾病中是必不可少的，因为它们可以防止乙酰胆碱的分解，从而增强认知功能。这篇综述提供了结构基序和控制乙酰胆碱酯酶药理活性的机制的全面分析，重点是药物化学策略，以提高效力，选择性和药代动力学性质。本文从乙酰胆碱酯酶在神经系统疾病中的生理作用开始，探讨了乙酰胆碱酯酶的历史演变，并强调了与催化、外周阴离子和变构结合位点的关键结构相互作用。讨论了计算建模、虚拟筛选和基于结构的药物设计方面的进展，以及多靶点定向配体和前药等新兴方法。此外，天然产物和药物再利用在鉴定新的AChEI支架中的重要性被强调，有助于化学多样性和药物发现的创新。通过整合计算工具、广泛的化学库和创新的设计策略，本综述确定了开发有效achei的有希望的方向。这些进展在解决神经退行性疾病的多面性和改善治疗干预方面具有巨大的潜力。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

Molecular Diversity 化学-化学综合

CiteScore

7.30

自引率

7.90%

发文量

219

审稿时长

2.7 months

期刊介绍： Molecular Diversity is a new publication forum for the rapid publication of refereed papers dedicated to describing the development, application and theory of molecular diversity and combinatorial chemistry in basic and applied research and drug discovery. The journal publishes both short and full papers, perspectives, news and reviews dealing with all aspects of the generation of molecular diversity, application of diversity for screening against alternative targets of all types (biological, biophysical, technological), analysis of results obtained and their application in various scientific disciplines/approaches including: combinatorial chemistry and parallel synthesis; small molecule libraries; microwave synthesis; flow synthesis; fluorous synthesis; diversity oriented synthesis (DOS); nanoreactors; click chemistry; multiplex technologies; fragment- and ligand-based design; structure/function/SAR; computational chemistry and molecular design; chemoinformatics; screening techniques and screening interfaces; analytical and purification methods; robotics, automation and miniaturization; targeted libraries; display libraries; peptides and peptoids; proteins; oligonucleotides; carbohydrates; natural diversity; new methods of library formulation and deconvolution; directed evolution, origin of life and recombination; search techniques, landscapes, random chemistry and more;