Gałęzowska Joanna, Chmielewska Ewa
Department of Inorganic Chemistry, Wrocław Medical University, Borowska 211A, 50-556, Wrocław, Poland.
Department of Bioorganic Chemistry, Faculty of Chemistry, Wrocław University of Science and Technology, Wybrzeże Wyspianskiego 27, 50-370, Wrocław, Poland.
Chem Biodivers. 2018 Oct;15(10):e1800272. doi: 10.1002/cbdv.201800272. Epub 2018 Aug 29.
Binding of bisphosphonates (BPs) to plasma proteins was investigated in the 1990s as a pharmacokinetic issue in order to fully understand bio-distribution of BP drugs which are successfully used for the treatment of several bone-related diseases. It has been hypothesized that binding to these proteins occurs with low to moderate affinity despite of unfavorable hydrophilicity of BPs, and Ca was identified as a strong catalyst of this binding. However, these studies mainly consisted in the separation and quantification of bound and unbound drug or protein fractions using chromatographic techniques without an outcome on the molecular level. Presented thermodynamic studies analyze the interactions of three N-BPs as well as their Ca complexes with bovine serum albumine (BSA) by means of isothermal calorimetry. The studies reveal spontaneous enthalpy favored interactions of N-BPs (amino-containing BPs) with BSA, which are enhanced by the presence of Ca ions up to ~15-fold, strongly depending on N-BP. Those are low affinity binding events, comparable to Ca -N-BP interactions, which most likely occur at Ca binding site(s). It is a first example of estimation of thermodynamic forces of interactions of free and calcium-bound N-BPs with albumin.
20世纪90年代，作为一个药代动力学问题，对双膦酸盐（BPs）与血浆蛋白的结合进行了研究，以便全面了解成功用于治疗几种骨相关疾病的BP药物的生物分布情况。据推测，尽管BPs具有不利的亲水性，但它们与这些蛋白质的结合亲和力较低至中等，并且钙被确定为这种结合的强催化剂。然而，这些研究主要包括使用色谱技术分离和定量结合和未结合的药物或蛋白质部分，而没有在分子水平上得出结果。本文提出的热力学研究通过等温滴定量热法分析了三种含氮双膦酸盐（N-BPs）及其钙络合物与牛血清白蛋白（BSA）的相互作用。研究表明，N-BPs（含氨基双膦酸盐）与BSA之间存在自发的焓有利相互作用，钙离子的存在可将这种相互作用增强约15倍，这在很大程度上取决于N-BP。这些是低亲和力结合事件，类似于钙-N-BP相互作用，很可能发生在钙结合位点。这是估计游离和钙结合的N-BPs与白蛋白相互作用的热力学力的第一个例子。
