Nabi Faisal, Ahmad Owais, Fatima Aiman, Ahmad Aamna, Sharma Jyoti, Khan Rizwan Hasan
Interdisciplinary Biotechnology Unit, Aligarh Muslim University, Aligarh, India.
Department of Botany, Aligarh Muslim University, Aligarh, India.
J Biomol Struct Dyn. 2024 Dec 5:1-13. doi: 10.1080/07391102.2024.2435641.
Alzheimer's disease (AD) is a progressive and largely incurable neurodegenerative disorder that affects millions of people worldwide. It is characterised by the accumulation of amyloid-beta plaques and neurofibrillary tangles in the brain. It is commenced by cleavage of amyloid precursor protein (APP) by β-secretase, β-site amyloid precursor protein cleaving enzyme (BACE1; also called Asp2, memapsin 2). Therefore, BACE1 is a prime target for developing therapeutics against AD. In this study, we have identified a small molecule that potentially inhibits the activity of BACE1 by interacting with the active site residues. Also, the flap region seems to be involved in enhancing the stability of the small molecule at the active site. We have used Umibecestat (CNP-520) as a positive control. Our results show that the identified molecule has a much better orientation at the active site of BACE1 than Umibecestat and inhibits by blocking the active site and modulating flap dynamics. We have utilised virtual high-throughput screening assay, ADME profiling, and blood-brain-barrier crossing ability to narrow down potential leads. The two shortlisted molecules were then subjected to atomistic molecular dynamics simulations study. Overall, our study proposes a much better inhibitor and a rational molecule for lead development against AD.
阿尔茨海默病（AD）是一种进行性且基本无法治愈的神经退行性疾病，影响着全球数百万人。其特征是大脑中β-淀粉样蛋白斑块和神经原纤维缠结的积累。它是由β-分泌酶，即β-位点淀粉样前体蛋白裂解酶（BACE1；也称为Asp2、膜天冬氨酸蛋白酶2）切割淀粉样前体蛋白（APP）引发的。因此，BACE1是开发抗AD治疗药物的主要靶点。在本研究中，我们鉴定出一种小分子，它可能通过与活性位点残基相互作用来抑制BACE1的活性。此外，瓣片区域似乎参与增强小分子在活性位点的稳定性。我们使用了乌米贝司他（CNP-520）作为阳性对照。我们的结果表明，所鉴定的分子在BACE1活性位点的取向比乌米贝司他好得多，并且通过阻断活性位点和调节瓣片动力学来发挥抑制作用。我们利用虚拟高通量筛选试验、药物代谢动力学（ADME）分析和血脑屏障穿越能力来缩小潜在的先导化合物范围。然后对这两个入围分子进行了原子分子动力学模拟研究。总体而言，我们的研究提出了一种更好的抑制剂以及一个用于开发抗AD先导药物的合理分子。
