Alzheimer's disease (AD), often referred to as the "diabetes of the brain", is intricately linked to insulin resistance. Metformin, a first-line antidiabetic drug, has been anticipated as a potential treatment for AD and is currently undergoing phase 3 clinical trials. The potential success of metformin in treating AD could herald a new era in the management of this debilitating disease, providing hope for millions of people affected worldwide. Despite this fact, the precise molecular mechanisms underlying the therapeutic effects of metformin on AD remain poorly understood. To pursue this, in this present work, we implement a comprehensive computational approach combining classical molecular dynamics (MD) simulations and the advanced enhanced sampling technique funnel metadynamics (FM) to explore the dynamics and affinity of metformin and acetylcholinesterase (AChE), a novel target for AD. The MD and FM simulations suggest that metformin induces significant configurational changes within the AChE, resulting in weak and nonspecific binding. Furthermore, the presence of metformin alters the conformational landscape of AChE causing the emergence of metastable states and less rigid binding patterns. The binding energies for the metformin-AChE complex are -4.89 ± 1.2 kcal/mol and -1.68 ± 0.2 kcal/mol, as estimated through the molecular mechanics Poisson-Boltzmann surface area (MMPBSA) and FM approaches, respectively. To elucidate the binding energy relevance calculated by MMPBSA and FM approach with experimental inhibitory potency, ΔG_exp is calculated using IC₅₀ value reported in prior experimental studies. ΔG_exp is estimated to be -3.59 kcal/mol. A comparison of these binding energy values with different methods highlights the moderate inhibitory potency of metformin toward AChE. This work provides molecular-level insights emphasizing the dynamic configurational changes induced by metformin within AChE and underscores its translational potential in the repurposing of AD.

阿尔茨海默病（AD）常被称为“脑部糖尿病”，与胰岛素抵抗密切相关。作为一线抗糖尿病药物，二甲双胍被预期可能成为治疗AD的潜在疗法，并正在接受第3阶段临床试验。如果二甲双胍在治疗AD方面取得成功，则预示着这一令人衰弱疾病的管理将迎来新时代，为全球数百万患者带来希望。尽管如此，二甲双胍对AD治疗效果的确切分子机制仍然不甚明了。

为了探究这一点，在本项工作中，我们采用了一种综合计算方法，结合经典分子动力学（MD）模拟和先进的增强采样技术漏斗元动态学（FM），来探索二甲双胍与乙酰胆碱酯酶（AChE，AD的新靶点）之间的动力学及亲和力。MD和FM的模拟结果表明，二甲双胍在AChE中引发了显著的构象变化，导致其弱而非特异性的结合。此外，二甲双胍的存在改变了AChE的构象景观，使其出现亚稳态并形成更松散的结合模式。通过分子力学泊松-玻尔兹曼表面面积（MMPBSA）和FM方法估计得到的二甲双胍-AChE复合物结合能分别为-4.89±1.2 kcal/mol和-1.68±0.2 kcal/mol。为了阐明由MMPBSA和FM方法计算出的结合能量与实验抑制效力的相关性，根据先前实验研究中报道的IC50值来计算ΔGexp，其估计值为-3.59 kcal/mol。不同方法得到的这些结合能数值比较表明了二甲双胍对AChE具有适度的抑制作用。

本项工作提供了分子水平上的见解，强调了二甲双胍在AChE中引发的动态构象变化，并突显其在AD再利用中的转化潜力。