Laboratory of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Coimbra, 3000-548 Coimbra, Portugal.
Center for Innovative Biomedicine and Biotechnology (CIBB), Center for Neuroscience and Cell Biology (CNC), University of Coimbra, 3004-504 Coimbra, Portugal.
Biomolecules. 2020 Apr 1;10(4):535. doi: 10.3390/biom10040535.
The treatment options for a patient diagnosed with Alzheimer's disease (AD) are currently limited. The cerebral accumulation of amyloid-β (Aβ) is a critical molecular event in the pathogenesis of AD. When the amyloidogenic β-secretase (BACE1) is inhibited, the production of Aβ peptide is reduced. Henceforth, the main goal of this study is the discovery of new small bioactive molecules that potentially reach the brain and inhibit BACE1. The work was conducted by a customized molecular modelling protocol, including pharmacophore-based and molecular docking-based virtual screening (VS). Structure-based (SB) and ligand-based (LB) pharmacophore models were designed to accurately screen several drug-like compound databases. The retrieved hits were subjected to molecular docking and in silico filtered to predict their ability to cross the blood-brain barrier (BBB). Additionally, 34 high-scoring compounds structurally distinct from known BACE1 inhibitors were selected for in vitro screening assay, which resulted in 13 novel hit-compounds for this relevant therapeutic target. This study disclosed new BACE1 inhibitors, proving the utility of combining computational and in vitro approaches for effectively predicting anti-BACE1 agents in the early drug discovery process.
目前，被诊断患有阿尔茨海默病（AD）的患者的治疗选择有限。脑内淀粉样蛋白-β（Aβ）的积累是 AD 发病机制中的关键分子事件。当淀粉样β-分泌酶（BACE1）被抑制时，Aβ肽的产生减少。因此，本研究的主要目标是发现新的具有潜在脑穿透能力并能抑制 BACE1 的小分子生物活性物质。这项工作是通过定制的分子建模方案进行的，包括基于药效团和基于分子对接的虚拟筛选（VS）。设计了基于结构（SB）和基于配体（LB）的药效团模型，以准确筛选几个类药性化合物数据库。检索到的命中物经过分子对接和计算机筛选，以预测它们穿过血脑屏障（BBB）的能力。此外，还选择了 34 种与已知 BACE1 抑制剂结构不同的高评分化合物进行体外筛选试验，这为该相关治疗靶点发现了 13 种新型命中化合物。这项研究揭示了新的 BACE1 抑制剂，证明了结合计算和体外方法在早期药物发现过程中有效预测抗 BACE1 药物的实用性。
