Laboratorio de Elucidación y Síntesis en Química Orgánica, ICUAP, BUAP, Puebla 72570, Mexico.
Laboratorio de Neuroquímica, FCQ, BUAP, Puebla 72570, Mexico.
Int J Mol Sci. 2023 May 3;24(9):8164. doi: 10.3390/ijms24098164.
The -secretase-1 enzyme (BACE-1) performs a key role in the production of beta-Amyloid protein (Aβ), which is associated with the development of Alzheimer's disease (AD). The inhibition of BACE-1 has been an important pharmacological strategy in the treatment of this neurodegenerative disease. This study aims to identify new potential candidates for the treatment of Alzheimer's with the help of in silico studies, such as molecular docking and ADME prediction, from a broad list of candidates provided by the DrugBank database. From this analysis, 1145 drugs capable of interacting with the enzyme with a higher coupling energy than Verubecestat were obtained, subsequently only 83 presented higher coupling energy than EJ7. Applying the oral route of administration as inclusion criteria, only 41 candidates met this requirement; however, 6 of them are associated with diagnostic tests and not treatment, so 33 candidates were obtained. Finally, five candidates were identified as possible BACE-1 inhibitors drugs: Fluphenazine, Naratriptan, Bazedoxifene, Frovatriptan, and Raloxifene. These candidates exhibit pharmacophore-specific features, including the indole or thioindole group, and interactions with key amino acids in BACE-1. Overall, this study provides insights into the potential use of in silico methods for drug repurposing and identification of new candidates for the treatment of Alzheimer's disease, especially those targeting BACE-1.
β-分泌酶 1 酶（BACE-1）在β-淀粉样蛋白（Aβ）的产生中发挥关键作用，Aβ 与阿尔茨海默病（AD）的发展有关。抑制 BACE-1 一直是治疗这种神经退行性疾病的重要药理学策略。本研究旨在通过计算机辅助研究，如分子对接和 ADME 预测，从 DrugBank 数据库提供的广泛候选物列表中，寻找新的治疗阿尔茨海默病的潜在候选物。通过这种分析，获得了 1145 种能够与酶相互作用且耦合能高于 Verubecestat 的药物，随后只有 83 种药物的耦合能高于 EJ7。将口服途径作为纳入标准，只有 41 种候选物符合此要求；然而，其中 6 种与诊断测试相关，而不是治疗，因此获得了 33 种候选物。最后，确定了 5 种可能的 BACE-1 抑制剂候选物：氟奋乃静、那拉曲坦、巴多昔芬、夫罗曲坦和雷洛昔芬。这些候选物表现出特定的药效基团特征，包括吲哚或硫代吲哚基团，并与 BACE-1 中的关键氨基酸相互作用。总体而言，本研究为药物重新利用和识别新的阿尔茨海默病治疗候选物提供了新的思路，特别是针对 BACE-1 的治疗方法。
