Ongtanasup Tassanee, Eawsakul Komgrit
Department of Applied Thai Traditional Medicine, School of Medicine, Walailak University, Nakhon Si Thammarat 80160, Thailand.
Center of Excellence in Tropical Pathobiology, Walailak University, Nakhon Si Thammarat 80160, Thailand.
Adv Pharmacol Pharm Sci. 2025 Mar 31;2025:5528793. doi: 10.1155/adpp/5528793. eCollection 2025.
Alzheimer's disease (AD) is a neurological condition that causes neurons and axons in the brain to deteriorate over time and in a specific pattern. The enzyme beta-secretase-1 (BACE-1) plays a crucial role in the onset and progression of AD. In silico approaches, or computer-aided drug design, have become useful tools for reducing the number of therapeutic candidates that need to be evaluated in human clinical trials. Finding chemicals that bind to BACE-1's active site and inhibit its activity is key for preventing AD. A pharmacophore model was developed in this study based on potent BACE-1 inhibitors previously identified, and subsequently employed to screen a commercially available compound database for similar compounds. ZINC35883784 was identified with high binding affinities and hydrogen bonding interactions. Moreover, similar properties to donepezil were found in a compound made by altering the structure of ZINC35883784 called (4R,5R)-2-[1-(2-ethylcyclohexyl)ethyl]-4-hydroxy-5-(4-hydroxybutyl)cyclohexanolate (M4). Compounds were tested for interactions with BACE-1 and favorable properties. Binding scores were confirmed after molecular docking. The assessment of drug-likeness was conducted utilizing Swiss ADME analysis. Molecular dynamics simulations assessed the stability of compound interactions with BACE-1. MMPBSA calculated binding free energy and contribution energy. Results showed that M4 had strong and steady interactions with BACE-1. M4 was also analyzed by predicted NMR and retrosynthesis. However, further experiments are needed to evaluate M4's potential as a BACE-1 inhibitor.
阿尔茨海默病（AD）是一种神经疾病，会导致大脑中的神经元和轴突随着时间推移以特定模式退化。β-分泌酶-1（BACE-1）在AD的发病和进展中起着关键作用。计算机辅助药物设计等计算机模拟方法已成为减少需要在人体临床试验中评估的治疗候选药物数量的有用工具。找到与BACE-1活性位点结合并抑制其活性的化学物质是预防AD的关键。本研究基于先前鉴定的强效BACE-1抑制剂开发了一种药效团模型，随后用于筛选市售化合物数据库以寻找类似化合物。ZINC35883784被鉴定具有高结合亲和力和氢键相互作用。此外，在一种通过改变ZINC35883784结构制成的化合物（4R,5R）-2-[1-(2-乙基环己基)乙基]-4-羟基-5-(4-羟基丁基)环己醇酸酯（M4）中发现了与多奈哌齐相似的性质。对化合物进行了与BACE-1相互作用和有利性质的测试。分子对接后确认了结合分数。利用瑞士ADME分析进行了类药性质评估。分子动力学模拟评估了化合物与BACE-1相互作用的稳定性。MMPBSA计算了结合自由能和贡献能量。结果表明，M4与BACE-1具有强烈且稳定的相互作用。还通过预测核磁共振和逆合成对M4进行了分析。然而，需要进一步的实验来评估M4作为BACE-1抑制剂的潜力。
