Department of Medicinal Chemistry, University of Zagreb Faculty of Pharmacy and Biochemistry, 10000 Zagreb, Croatia.
Laboratory of Computational Modelling of Drugs, South Ural State University, 454008 Chelyabinsk, Russia.
Int J Mol Sci. 2020 Aug 10;21(16):5740. doi: 10.3390/ijms21165740.
Human serum albumin (HSA) is the most abundant carrier protein in the human body. Competition for the same binding site between different ligands can lead to an increased active concentration or a faster elimination of one or both ligands. Indomethacin and quercetin both bind to the binding site located in the IIA subdomain. To determine the nature of the HSA-indomethacin-quercetin interactions, spectrofluorometric, docking, molecular dynamics studies, and quantum chemical calculations were performed. The results show that the indomethacin and quercetin binding sites do not overlap. Moreover, the presence of quercetin does not influence the binding constant and position of indomethacin in the pocket. However, binding of quercetin is much more favorable in the presence of indomethacin, with its position and interactions with HSA significantly changed. These results provide a new insight into drug-drug interactions, which can be important in situations when displacement from HSA or other proteins is undesirable or even desirable. This principle could also be used to deliberately prolong or shorten the xenobiotics' half-life in the body, depending on the desired outcomes.
人血清白蛋白（HSA）是人体内最丰富的载体蛋白。不同配体之间对同一结合位点的竞争可能导致一种或两种配体的活性浓度增加或消除速度加快。吲哚美辛和槲皮素都与位于 IIA 亚结构域的结合位点结合。为了确定 HSA-吲哚美辛-槲皮素相互作用的性质，进行了荧光光谱、对接、分子动力学研究和量子化学计算。结果表明，吲哚美辛和槲皮素的结合位点不重叠。此外，槲皮素的存在并不影响口袋中吲哚美辛的结合常数和位置。然而，在存在吲哚美辛的情况下，槲皮素的结合更有利，其位置和与 HSA 的相互作用发生了显著变化。这些结果为药物-药物相互作用提供了新的见解，这在从 HSA 或其他蛋白质中置换不希望或甚至需要的情况下可能很重要。这一原则也可以根据预期的结果用于故意延长或缩短异生物质在体内的半衰期。
