Department of Chemical and Environmental Process Engineering , Budapest University of Technology and Economics , Műegyetem rakpart 3 , 1111 Budapest , Hungary.
Chemistry Department , Gedeon Richter Plc. , Gyömrői út. 19-21 , 1107 Budapest , Hungary.
J Med Chem. 2020 Feb 27;63(4):1763-1774. doi: 10.1021/acs.jmedchem.0c00046. Epub 2020 Feb 11.
The knowledge on human serum albumin (HSA) binding is of utmost importance as it affects pharmacokinetic behavior and bioavailability of drugs. In this article, we report a novel method to screen for ionizable molecules with high HSA binding affinity based on p shifts using UV-pH titration. We investigated the HSA binding of 27 drugs and compared the results to experimental data from conventional methods. In most cases, significant shifts (Δp > 0.1) were observed for drugs with high HSA binding, while no change could be detected for low-affinity binders. We showed the pivotal role of ionization centers in the formation of strong interactions between drug and HSA using molecular docking studies. We also verified our findings by testing five modified analogues designed by structural considerations. Significant decreases in their HSA binding proved that the UV-pH titration method combined with an in silico support can be used as a medicinal chemistry tool to assist rational molecular design.
本文报道了一种基于 UV-pH 滴定的新方法，通过 p 移位筛选与人类血清白蛋白（HSA）具有高结合亲和力的可离子化分子。我们研究了 27 种药物与 HSA 的结合，并将结果与传统方法的实验数据进行了比较。在大多数情况下，与 HSA 具有高结合亲和力的药物观察到明显的 p 移位（Δp > 0.1），而低亲和力结合物则没有变化。通过分子对接研究，我们表明了电离中心在药物与 HSA 之间形成强相互作用中的关键作用。我们还通过测试根据结构考虑设计的五个修饰类似物验证了我们的发现。它们与 HSA 结合的显著降低证明了 UV-pH 滴定法结合计算机辅助支持可作为一种药物化学工具，用于辅助合理的分子设计。
