Background: Alzheimer's Disease (AD) represents a neurodegenerative disorder characterized by cognitive and behavioral impairments significantly hindering social and occupational functioning. Melatonin, a hormone pivotal in regulating the body's intrinsic circadian rhythm, also acts as a catalyst in the breakdown of beta-amyloid deposits, offering a promising therapeutic approach for AD. The upregulation of Brain and Muscle ARNT-Like 1 (Bmal1) gene expression, stimulated by melatonin, emerges as a potential contributor to AD intervention. Current pharmacological interventions, such as FDA-approved cholinesterase inhibitors and the recently authorized monoclonal antibody, Lecanemab, are utilized in AD management. However, the connection between these medications and Bmal1 remains insufficiently explored. Objective: This study aims to investigate the molecular effects of FDA-endorsed drugs on the CLOCK: Bmal1 dimer. Furthermore, considering the interactions between melatonin and Bmal1, this research explores the potential synergistic efficacy of combining these pharmaceutical agents with melatonin for AD treatment. Methods: Using molecular docking and MM/PBSA methodologies, this research determines the binding affinities of drugs within the Bmal1 binding site, constructing interaction profiles. Results: The findings reveal that, among FDA-approved drugs, galanthamine and donepezil demonstrate notably similar binding energy values to melatonin, interacting within the Bmal1 binding site through analogous amino acid residues and functional groups. Conclusion: A novel therapeutic approach emerges, suggesting the combination of melatonin with Lecanemab as a monoclonal antibody therapy. Importantly, prior research has not explored the effects of FDA-approved drugs on Bmal1 expression or their potential for synergistic effects.

中文翻译：

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超越传统疗法：通过 CLOCK/BMAL1 相互作用治疗阿尔茨海默病的分子动力学

背景：阿尔茨海默病（AD）是一种神经退行性疾病，其特征是认知和行为障碍，严重阻碍社会和职业功能。褪黑激素是调节人体内在昼夜节律的关键激素，也可作为分解 β-淀粉样蛋白沉积物的催化剂，为 AD 提供了一种有前途的治疗方法。褪黑激素刺激大脑和肌肉 ARNT 样 1 (Bmal1) 基因表达上调，成为 AD 干预的潜在因素。目前的药物干预措施，如 FDA 批准的胆碱酯酶抑制剂和最近授权的单克隆抗体 Lecanemab，被用于 AD 治疗。然而，这些药物与 Bmal1 之间的联系尚未得到充分探索。目的：本研究旨在研究 FDA 认可的药物对 CLOCK：Bmal1 二聚体的分子影响。此外，考虑到褪黑激素和 Bmal1 之间的相互作用，本研究探讨了这些药物与褪黑激素联合治疗 AD 的潜在协同功效。方法：本研究使用分子对接和 MM/PBSA 方法，确定 Bmal1 结合位点内药物的结合亲和力，构建相互作用谱。结果：研究结果表明，在 FDA 批准的药物中，加兰他敏和多奈哌齐与褪黑激素的结合能值非常相似，通过类似的氨基酸残基和官能团在 Bmal1 结合位点内相互作用。结论：出现了一种新的治疗方法，表明褪黑激素与 Lecanemab 联合作为单克隆抗体疗法。重要的是，之前的研究尚未探讨 FDA 批准的药物对 Bmal1 表达的影响或其协同作用的潜力。