利用分子建模和模拟方法探索小分子作为潜在BACE1蛋白抑制剂治疗淀粉样脑血管病

IF 2.6 3区 综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES
PLoS ONE Pub Date : 2025-03-21 eCollection Date: 2025-01-01 DOI:10.1371/journal.pone.0317716
Zhizhong Wang, Zhiyong Li, Ailong Lin, Qing Zhang, Yingchun Chen, Bizhou Bie, Juanjuan Feng
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引用次数: 0

摘要

淀粉样脑血管病主要由淀粉样β (Aβ)肽的积累引起,与阿尔茨海默病等神经退行性疾病有着复杂的联系。BACE1 (β位点淀粉样蛋白前体蛋白切割酶1)在a β的产生中起关键作用,使其成为关键的治疗靶点。在目前的工作中,ChemDiv数据库的一个包含44085个化合物的CNS文库对BACE1蛋白进行了筛选。首先,构建基于结构的药效团假设,然后进行虚拟筛选,筛选后的hit与BACE1蛋白对接,确定最佳结合模式。对接结果使用滑动gscore和对接分子的化学相互作用进行检验。采用-5 kcal/mol的临界值选择高结合亲和力的命中。根据滑翔得分,总共选择了7个目标。此外,研究了对接配体的可能结合机制,发现所有7个选择的配体在预测的蛋白质结合口袋中占据相同的位置。化合物的生物活性评分表明所选化合物具有先导化合物的特征。对所选化合物的毒性风险和ADMET特征进行预测,并选择J032-0080、SC13-0774、V030-0915和V006-5608 4个化合物进行稳定性分析。选择的击中点非常稳定,并且与BACE1口袋结合强烈,并且使用MD模型评估RMSD, RMSF和蛋白质-配体相互作用引起的构象变化。同样,主成分分析也揭示了大量的氢键静态数目。MM/GBSA结合自由能图显示了选择的命中与BACE1结合的显著能量贡献。结合自由能图表明,这些命中具有较高的结合亲和力。因此,这些hit可以作为生物物理研究中的先导化合物来限制BACE1蛋白的生物活性。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Exploration of small molecules as inhibitors of potential BACE1 protein to treat amyloid cerebrovascular disease by employing molecular modeling and simulation approaches.

Amyloid cerebrovascular disease, primarily driven by the accumulation of amyloid-beta (Aβ) peptides, is intricately linked to neurodegenerative disorders like Alzheimer's disease. BACE1 (beta-site amyloid precursor protein cleaving enzyme 1) plays a critical role in the production of Aβ, making it a key therapeutic target. In the current work, a CNS library of ChemDiv database containing 44085 compounds was screened against the BACE1 protein. Initially, a structure-based pharmacophore hypothesis was constructed, followed by virtual screening, with the screened hits docked to the BACE1 protein to determine the optimal binding modes. The docking results were examined using the glide gscore and chemical interactions of the docked molecules. The cutoff value of -5 kcal/mol was used to select hits with high binding affinities. A total of seven hits were chosen based on the glide g score. Furthermore, the possible binding mechanisms of the docked ligands were investigated, and it was discovered that all seven selected ligands occupied the same site in the predicted binding pocket of protein. The bioactivity scores of the compounds demonstrated that the chosen compounds possess the features of lead compounds. The toxicity risks and ADMET features of the selected hits were anticipated, and four compounds, J032-0080, SC13-0774, V030-0915, and V006-5608 were chosen for stability analysis. The selected hits were extremely stable and strongly bound to the BACE1 pocket, and conformational changes caused by RMSD, RMSF, and protein-ligand interactions were assessed using MD modeling. Similarly, principal component analysis revealed a large static number of hydrogen bonds. The MM/GBSA binding free energies maps revealed a significant energy contribution in the binding of selected hits to BACE1. The binding free energy landscapes indicated that the hits were bound with a high binding affinity. Thus, the hits could serve as lead compounds in biophysical investigations to limit the biological activity of the BACE1 protein.

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来源期刊
PLoS ONE
PLoS ONE 生物-生物学
CiteScore
6.20
自引率
5.40%
发文量
14242
审稿时长
3.7 months
期刊介绍: PLOS ONE is an international, peer-reviewed, open-access, online publication. PLOS ONE welcomes reports on primary research from any scientific discipline. It provides: * Open-access—freely accessible online, authors retain copyright * Fast publication times * Peer review by expert, practicing researchers * Post-publication tools to indicate quality and impact * Community-based dialogue on articles * Worldwide media coverage
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