阿尔茨海默病的计算机辅助药物设计:最新进展和未来展望。

IF 3.3 4区 医学 Q3 CHEMISTRY, MEDICINAL
Suman Rohilla, Garima Goyal
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引用次数: 0

摘要

阿尔茨海默病(AD)是一种以认知功能下降和记忆丧失为特征的神经退行性疾病,主要由胆碱能功能障碍、淀粉样斑块的积累、tau缠结的形成和神经元的进行性变性引起。虽然现有的治疗方法提供有限的症状缓解,但它们并不能有效地阻止或逆转疾病的潜在进展,这是阿尔茨海默病研究的一个重大全球挑战。开发阿尔茨海默病的治疗策略仍然很复杂,主要是因为目前的药物无法显著减缓神经退行性变。传统的药物发现过程往往漫长、昂贵且效率低下,使寻找有效治疗方法变得更加复杂。为了克服这些障碍,研究人员已经转向将计算方法与传统药物设计技术相结合。这些集成的方法通过显著减少时间和成本,帮助加快发现过程。本综述深入探讨了阿尔茨海默病的潜在生理和病理机制,同时确定了潜在的药物靶点,如乙酰胆碱酯酶、丁酰胆碱酯酶、β-分泌酶(BACE-1)、A2A腺苷受体、Dickkopf-1蛋白、糖原合成酶激酶3β、吲哚胺2,3-双加氧酶、单胺氧化酶b、NMDA受体、Wnt抑制因子、环非依赖性激酶5、谷氨酰胺环化酶和组织蛋白酶b。此外,本文还研究了各种计算机辅助药物设计(CADD)方法,包括基于结构和基于配体的方法、虚拟筛选、药效团建模、分子建模和模拟技术。这些计算策略在阿尔茨海默病的研究中发挥着越来越重要的作用,特别是在药物发现方面。通过研究有前途的候选药物和靶向阿尔茨海默病发病机制中关键蛋白的先导分子,本文重点介绍了它们与这些靶点的结合模式,并评估了开发有效临床候选药物所必需的化学性质。其目的是为研究人员提供关键的见解和工具,以设计具有成功治疗阿尔茨海默病所需的必要化学和物理特性的新化合物。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Computer-aided Drug Design for Alzheimer's Disease: Recent Advancements and Future Perspectives.

Alzheimer's disease (AD) is a neurodegenerative disorder marked by a decline in cognitive function and memory loss, primarily resulting from cholinergic dysfunction, the accumulation of amyloid plaques, the formation of tau tangles, and the progressive degeneration of neurons. While existing treatments offer limited symptomatic relief, they do not effectively halt or reverse the underlying progression of the disease, presenting a major global challenge in Alzheimer's research. Developing therapeutic strategies for AD remains complex, largely due to the inability of current medications to significantly slow neurodegeneration. Traditional drug discovery processes are often lengthy, costly, and inefficient, further complicating the search for effective treatments. To overcome these obstacles, researchers have turned to a combination of computational approaches alongside conventional drug design techniques. These integrated methodologies help accelerate the discovery process by significantly reducing both time and costs. This review delves into the underlying physiological and pathological mechanisms of Alzheimer's disease, while identifying potential drug targets such as acetylcholinesterase, butyrylcholinesterase, β-Secretase (BACE-1), A2A adenosine receptor, Dickkopf-1 protein, glycogen synthase kinase-3β, indoleamine 2,3-dioxygenase, monoamine oxidase-B, NMDA receptor, Wnt inhibitory factor, cyclindependent kinase-5, glutaminyl cyclase, and cathepsin-B. Furthermore, the review examines various computer-aided drug design (CADD) methodologies, including structure-based and ligandbased approaches, virtual screening, pharmacophore modeling, molecular modelling, and simulation techniques. These computational strategies are playing an increasingly important role in Alzheimer's research, particularly in drug discovery. By investigating promising drug candidates and lead molecules that target key proteins involved in Alzheimer's pathogenesis, the review highlights their binding modes with these targets and assesses the chemical properties essential for the development of effective clinical candidates. The aim is to provide researchers with critical insights and tools to design novel compounds with the necessary chemical and physical characteristics required for the successful treatment of Alzheimer's disease.

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来源期刊
CiteScore
6.40
自引率
2.90%
发文量
186
审稿时长
3-8 weeks
期刊介绍: Current Topics in Medicinal Chemistry is a forum for the review of areas of keen and topical interest to medicinal chemists and others in the allied disciplines. Each issue is solely devoted to a specific topic, containing six to nine reviews, which provide the reader a comprehensive survey of that area. A Guest Editor who is an expert in the topic under review, will assemble each issue. The scope of Current Topics in Medicinal Chemistry will cover all areas of medicinal chemistry, including current developments in rational drug design, synthetic chemistry, bioorganic chemistry, high-throughput screening, combinatorial chemistry, compound diversity measurements, drug absorption, drug distribution, metabolism, new and emerging drug targets, natural products, pharmacogenomics, and structure-activity relationships. Medicinal chemistry is a rapidly maturing discipline. The study of how structure and function are related is absolutely essential to understanding the molecular basis of life. Current Topics in Medicinal Chemistry aims to contribute to the growth of scientific knowledge and insight, and facilitate the discovery and development of new therapeutic agents to treat debilitating human disorders. The journal is essential for every medicinal chemist who wishes to be kept informed and up-to-date with the latest and most important advances.
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