Structure-Based Virtual Screening and Biological Characterization of Novel BACE-1 and Amyloid-β Aggregation Inhibitors.

IF 3.6 4区医学 Q2 CHEMISTRY, MEDICINAL ChemMedChem Pub Date : 2024-12-07 DOI:10.1002/cmdc.202400685

Ankita Sharma, Madhusmita Nayak, Shikha Thakur, Hemant R Jadhav, Sandip B Bharate

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Abstract

Alzheimer's disease (AD) is a complex neurodegenerative disorder having limited treatment options. The beta-site APP cleaving enzyme 1 (BACE-1) is a key target for therapeutic intervention in Alzheimer's disease. To discover new scaffolds for BACE-1 inhibitors, a ChemBridge DIVERSet library of 20,000 small molecules was employed to structure-based virtual screening. The top 45 compounds, based on docking scores and binding affinities, were tested for BACE-1 inhibitory activity using a FRET assay. Four compounds, 18 (5353320), 20 (5262831), 29 (5784196) and 32 (5794006) demonstrated more than 35 % inhibitory activity at 10 μM. Notably, pyrazole-5-carbohydrazide 29 (5784196) exhibited BACE-1 inhibition with an IC₅₀ value of 14.5 μM and a ki value of 0.25 μM. Additionally, it also inhibits the self-aggregation of β-amyloid, with IC₅₀ value of 14.87 μM. Molecular modeling and dynamics simulations provided insights into its interaction pattern and stability of the enzyme-inhibitor complex. These findings suggest that virtual screening is an efficient and cost-effective method for identifying potential leads for AD.

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新型BACE-1和淀粉样蛋白-β聚集抑制剂基于结构的虚拟筛选和生物学特性研究。

阿尔茨海默病（AD）是一种复杂的神经退行性疾病，治疗方案有限。β -位点APP切割酶1 （BACE-1）是阿尔茨海默病治疗干预的关键靶点。为了发现BACE-1抑制剂的新支架，使用ChemBridge DIVERSet包含20,000个小分子的文库进行基于结构的虚拟筛选。根据对接得分和结合亲和力，使用FRET检测前45个化合物的BACE-1抑制活性。其中4个化合物18（5353320）、20（5262831）、29（5784196）和32（5794006）在10µM下的抑制活性超过35%。值得注意的是，pyrazole-5- carbohydraide 29（5784196）的IC50值为14.5 μM， ki值为0.25 μM。此外，它还能抑制β-淀粉样蛋白的自聚集，IC50值为14.87µM。分子模型和动力学模拟提供了对其相互作用模式和酶抑制剂复合物稳定性的见解。这些发现表明，虚拟筛查是识别AD潜在线索的有效和经济的方法。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

ChemMedChem 医学-药学

CiteScore

6.70

自引率

2.90%

发文量

280

审稿时长

1 months

期刊介绍： Quality research. Outstanding publications. With an impact factor of 3.124 (2019), ChemMedChem is a top journal for research at the interface of chemistry, biology and medicine. It is published on behalf of Chemistry Europe, an association of 16 European chemical societies. ChemMedChem publishes primary as well as critical secondary and tertiary information from authors across and for the world. Its mission is to integrate the wide and flourishing field of medicinal and pharmaceutical sciences, ranging from drug design and discovery to drug development and delivery, from molecular modeling to combinatorial chemistry, from target validation to lead generation and ADMET studies. ChemMedChem typically covers topics on small molecules, therapeutic macromolecules, peptides, peptidomimetics, and aptamers, protein-drug conjugates, nucleic acid therapies, and beginning 2017, nanomedicine, particularly 1) targeted nanodelivery, 2) theranostic nanoparticles, and 3) nanodrugs. Contents ChemMedChem publishes an attractive mixture of: Full Papers and Communications Reviews and Minireviews Patent Reviews Highlights and Concepts Book and Multimedia Reviews.