基于高精度理论计算的人血清白蛋白与多酚化合物结合关系的机制研究

Human serum albumin (HSA), the most abundant transport protein for endogenous and exogenous compounds in plasma, plays a crucial role in the pharmacokinetic and pharmacodynamic profile of a wide variety of ligands. Binding affinity for HSA has received a great deal of attention, due to a significant impact in understanding of drug metabolism process and promoting new drug design and development. Although the existing researches enable a deep understanding of HSA-drug interactions to be possible, the details of molecular mechanisms of interactions and the kinetic and thermodynamic properties of protein-ligand complex cannot be experimentally detected at an atomic level. Recently, molecular modeling has been widely used in the field of biomedicine, for it can provide the atomistic level description of the protein-ligand interactions, and has an important role in guiding the molecular modification and drug design. In this work, the molecular mechanisms of HSA and a series of polyphenol compounds with different hydroxyl replacements, including the effects of the binding of fatty acids or metal ion to HSA-polyphenol complex, are going to be investigated in details by performing the molecular docking and high-accuracy molecular dynamics simulations with the AMOEBA polarizable force field and metadynamics on GPU platform, and be validated by ultrafiltration-HPLC method. In addition, related apparent volume of distribution parameter prediction researches are also going to be carried out. The present project would give valuable information for the researches in new drug design.

人血清白蛋白(Human Serum Albumin, HSA)与药物之间的作用直接影响药物的药代动力学和药效动力学性质，对二者的研究有助于了解药物的代谢过程并促进新药的开发。尽管现有的研究加深了人们对HSA与药物相互作用的理解，但实验上尚不能真正从原子水平上揭示相互作用细节以及复合物的动力学和热力学性质。分子模拟不仅可以提供具体作用信息，而且对药物分子改造及优化具有重要的指导作用。本项目利用基于GPU硬件加速的全原子AMOEBA可极化分子力场与增强型采样技术Metadynamics相结合的高精度分子模拟方法以及超滤-高效液相色谱法，探讨HSA与多酚化合物之间特异的结合方式及详细的结构信息，以及不同羟基取代状态对二者相互作用的影响；探讨脂肪酸和金属离子等影响二者结合的分子机理；在此基础上进一步预测多酚类黄酮化合物的表观分布容积等药代动力学参数，以期为药物开发早期的成药性提供一定的理论基础。

人血清白蛋白(Human Serum Albumin, HSA)与药物之间的作用直接影响药物的药代动力学和药效动力学性质，对二者的研究有助于了解药物的代谢过程并促进新药的开发。尽管现有的研究加深了人们对HSA与药物相互作用的理解，但实验上尚不能真正从原子水平上揭示相互作用细节以及复合物的动力学和热力学性质。本项目综合利用分子对接和分子模拟等理论计算方法，结合超滤-高效液相色谱法，从结构和能量等方面研究了HSA与结构相似的多酚化合物之间特异的结合方式及详细的结构信息，以及不同羟基取代状态对二者相互作用行为差异的影响。研究发现多酚类化合物结合在HSA的Site I并与这个疏水性结合口袋周围多个氨基酸残基发生疏水相互作用和氢键相互作用，B环上邻位羟基取代和C环上的3-没食子酸酯取代在多酚类化合物的高亲和力上发挥重要作用，且随着羟基数目的增加其血浆蛋白的结合能力越强。本项目的研究将会为该类药物的后续开发及临床应用提供一定的理论依据。

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