糖尿病药物代谢物的结构、动力学和生物活性
Towards Understanding the Structure, Dynamics and Bio-activity of Diabetic Drug Metformin
摘要：
小分子经常被发现表现出非常多样化的生物活性。Metalloy就是其中之一。它被广泛用作2型糖尿病的抗糖尿病药物。除此之外，盐酸二甲双胍还具有抗肿瘤活性，可提高某些类型癌症（即结直肠癌、乳腺癌、胰腺癌和前列腺癌）患者的生存率。然而，二甲双胍的结构和动力学的理论研究尚未得到充分探索。本文通过实验、量子化学计算和原子分子动力学模拟，研究了盐酸二甲双胍三种单质子化形式的结构和动力学特征。我们验证我们的力场通过比较模拟结果的实验结果。然而，我们发现非平面互变异构形式是最稳定的。金属间化合物与周围的水分子形成强氢键，其溶剂化动力学表现出独特的特征。由于扩展的正电荷分布，二甲双胍具有作为多个靶点的永久阳离子伴侣的特征。利用紫外光谱、圆二色谱、荧光光谱和偏微分方程模拟研究了它与DNA的相互作用和结合能力。我们发现了一种非插入的相互作用模式。金属间化合物在几十纳秒内可行地形成小/大沟结合状态，优选地具有AT富集结构域。当它与DNA的小沟结合时，观察到结合自由能的显著降低。
英文摘要：
Small molecules are often found to exhibit extraordinarily diverse biological activities. Metformin is one of them. It is widely used as anti-diabetic drug for type-two diabetes. In addition to that, metformin hydrochloride shows anti-tumour activities and increases the survival rate of patients suffering from certain types of cancer namely colorectal, breast, pancreas and prostate cancer. However, theoretical studies of structure and dynamics of metformin have not yet been fully explored. In this work, we investigate the characteristic structural and dynamical features of three mono-protonated forms of metformin hydrochloride with the help of experiments, quantum chemical calculations and atomistic molecular dynamics simulations. We validate our force field by comparing simulation results to that of the experimental findings. Nevertheless, we discover that the non-planar tautomeric form is the most stable. Metformin forms strong hydrogen bonds with surrounding water molecules and its solvation dynamics show unique features. Because of an extended positive charge distribution, metformin possesses features of being a permanent cationic partner toward several targets. We study its interaction and binding ability with DNA using UV spectroscopy, circular dichroism, fluorimetry and metadynamics simulation. We find a non-intercalating mode of interaction. Metformin feasibly forms a minor/major groove-bound state within a few tens of nanoseconds, preferably with AT rich domains. A significant decrease in the free-energy of binding is observed when it binds to a minor groove of DNA.
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