College of Pharmacy and Biological Engineering, Chengdu University, Chengdu 610106, China.
College of Pharmacy and Biological Engineering, Chengdu University, Chengdu 610106, China.
Eur J Med Chem. 2018 Feb 25;146:245-250. doi: 10.1016/j.ejmech.2018.01.064. Epub 2018 Feb 4.
The interaction between benproperine (BEN) and human serum albumin (HSA) has been simulatively and experimentally investigated based on docking, fluorometric, thermodynamic, and spectroscopic approach. The blind Autodock docking study first recognized the hydrophobic cavity of HSA at Domain IB as the probable binding site for BEN. BEN bound to HSA via a static quenching mechanism, resulting in the formation of BEN-HSA complex confirmed by fluorescence quenching and time-resolved fluorescence. Fluorescence titration and isothermal titration calorimetry (ITC) revealed that the binding mode between BEN and HSA owning moderate affinity (binding constant at 10 magnitude) was mainly driven by electrostatic attraction and hydrophobic interaction. Circular dichroism (CD) spectra suggested upon Addition of BEN induced the conformational changes on HSA with α-helix decreasing. Due to the conformational rearrangements, BEN-HSA complex was stabilized by several non-covalent bonds. This work first clarified the progress in binding mechanism of benproperine with human serum albumin and then provided fresh insights into this drug transportation and metabolism.
本研究基于对接、荧光、热力学和光谱方法，模拟和实验研究了苯丙哌林（BEN）与人血清白蛋白（HSA）之间的相互作用。盲目的 Autodock 对接研究首先识别出 HSA 结构域 IB 中的疏水腔是 BEN 的可能结合部位。BEN 通过静态猝灭机制与 HSA 结合，通过荧光猝灭和时间分辨荧光证实了 BEN-HSA 复合物的形成。荧光滴定和等温热力学滴定（ITC）表明，BEN 与 HSA 之间的结合模式具有中等亲和力（结合常数为 10 数量级），主要由静电吸引和疏水相互作用驱动。圆二色性（CD）光谱表明，BEN 的加入诱导 HSA 的构象发生变化，α-螺旋减少。由于构象重排，BEN-HSA 复合物通过几种非共价键稳定。这项工作首次阐明了苯丙哌林与人体血清白蛋白结合的作用机制，为进一步了解该药物的转运和代谢提供了新的思路。
