Department of Biotechnology, Institute of Engineering and Technology, Dr. A.P.J. Abdul Kalam Technical University, Lucknow, Uttar Pradesh, 226021, India.
School of Computational & Integrative Sciences, Jawaharlal Nehru University, New Delhi, 110067, India.
J Mol Model. 2021 Jan 30;27(2):58. doi: 10.1007/s00894-021-04679-3.
Alzheimer's disease (AD) is a type of brain disorder, wherein a person experiences gradual memory loss, state of confusion, hallucination, agitation, and personality change. AD is marked by the presence of extracellular amyloid plaques and intracellular neurofibrillary tangles (NFTs) and synaptic losses. Increased cases of AD in recent times created a dire need to discover or identify chemical compounds that can cease the development of AD. This study focuses on finding potential drug molecule(s) active against β-secretase, also known as β-site amyloid precursor protein cleaving enzyme 1 (BACE1). Clustering analysis followed by phylogenetic studies on microarray datasets retrieved from GEO browser showed that BACE1 gene has genetic relatedness with the RCAN1 gene. A ligand library comprising 60 natural compounds retrieved from literature and 25 synthetic compounds collected from DrugBank were screened. Further, 350 analogues of potential parent compounds were added to the library for the docking purposes. Molecular docking studies identified 11-oxotigogenin as the best ligand molecule. The compound showed the binding affinity of - 11.1 Kcal/mole and forms three hydrogen bonds with Trp124, Ile174, and Arg176. The protein-ligand complex was subjected to 25 ns molecular dynamics simulation and the potential energy of the complex was found to be - 1.24579e+06 Kcal/mole. In this study, 11-oxotigogenin has shown promising results against BACE1, which is a leading cause of AD, hence warrants for in vitro and in vivo validation of the same. In addition, in silico identification of 11-oxotigogenin as a potential anti-AD compound paves the way for designing of chemical scaffolds to discover more potent BACE1 inhibitors.Graphical abstract.
阿尔茨海默病（AD）是一种脑紊乱疾病，患者会逐渐出现记忆丧失、意识混乱、幻觉、烦躁不安和性格改变等症状。AD 的特征是细胞外淀粉样斑块和细胞内神经原纤维缠结（NFTs）以及突触丧失的存在。最近 AD 病例的增加迫切需要发现或识别可以阻止 AD 发展的化学化合物。本研究专注于寻找针对β-分泌酶（也称为β-位点淀粉样前体蛋白裂解酶 1（BACE1））有活性的潜在药物分子。通过对从 GEO 浏览器检索到的微阵列数据集进行聚类分析和系统发育研究，表明 BACE1 基因与 RCAN1 基因具有遗传相关性。从文献中检索到的包含 60 种天然化合物的配体库和从 DrugBank 收集的 25 种合成化合物进行筛选。此外，还为对接目的向库中添加了 350 种潜在母体化合物的类似物。分子对接研究确定了 11-氧代替告依春是最佳配体分子。该化合物表现出 - 11.1 Kcal/mole 的结合亲和力，并与 Trp124、Ile174 和 Arg176 形成三个氢键。将蛋白质-配体复合物进行 25 ns 分子动力学模拟，发现复合物的势能为 - 1.24579e+06 Kcal/mole。在这项研究中，11-氧代替告依春对 BACE1 表现出有希望的结果，BACE1 是 AD 的主要原因，因此需要对其进行体外和体内验证。此外，通过计算鉴定 11-氧代替告依春作为一种潜在的抗 AD 化合物，为设计化学支架以发现更有效的 BACE1 抑制剂铺平了道路。
