Molecular Sciences Institute, School of Chemistry, University of the Witwatersrand, Johannesburg PO WITS 2050, South Africa.
Molecules. 2023 Nov 7;28(22):7466. doi: 10.3390/molecules28227466.
Human serum albumin (HSA) efficiently transports drugs in vivo: most are organic. Therefore, it is important to delineate the binding of small molecules to HSA. Here, for the first time, we show that HSA binding depends not only on the identity of the d metal ion, Ni or Pd, of their complexes with bis(pyrrole-imine), HPrPyrr, but on the pH level as well. Fluorescence quenching data for native and probe-bound HSA showed that sites close to Trp-214 (subdomain IIA) are targeted. The affinity constants, K, ranged from ~3.5 × 10 M to ~1 × 10 M at 37 °C, following the order Pd(PrPyrr) > Ni(PrPyrr) at pH levels of 4 and 7; but Ni(PrPyrr) > Pd(PrPyrr) at a pH level of 9. Ligand uptake is enthalpically driven, dependent mainly on London dispersion forces. The induced CD spectra for the protein-bound ligands could be simulated by hybrid QM:MM TD-DFT methods, allowing us to delineate the binding site of the ligands and to prove that the metal chelates neither decompose nor demetallate after uptake by HSA. The transport and delivery of the metal chelates by HSA in vivo is therefore feasible.
人血清白蛋白（HSA）在体内有效地转运药物：大多数药物都是有机的。因此，阐明小分子与 HSA 的结合非常重要。在这里，我们首次表明，HSA 结合不仅取决于 d 金属离子（Ni 或 Pd）及其与双（吡咯-亚胺）、HPrPyrr 的配合物的身份，还取决于 pH 值。对于天然和探针结合的 HSA 的荧光猝灭数据表明，靠近色氨酸 214（亚域 IIA）的位点是靶标。在 37°C 下，亲和常数 K 的范围从3.5×10^M 到1×10^M，在 pH 值为 4 和 7 时，Pd(PrPyrr) > Ni(PrPyrr)；但在 pH 值为 9 时，Ni(PrPyrr) > Pd(PrPyrr)。配体摄取是焓驱动的，主要依赖于伦敦色散力。蛋白结合配体的诱导 CD 光谱可以通过混合 QM:MM TD-DFT 方法进行模拟，使我们能够描绘配体的结合位点，并证明金属螯合物在被 HSA 摄取后既不会分解也不会脱金属。因此，金属螯合物在体内通过 HSA 的运输和递释是可行的。
