Paolillo Maddalena, Ferraro Giarita, Gumerova Nadiia I, Pisanu Federico, Garribba Eugenio, Rompel Annette, Merlino Antonello
Department of Chemical Sciences, University of Naples Federico II Complesso Universitario di Monte Sant'Angelo Via Cintia I-80126 Napoli Italy
Universität Wien, Fakultät für Chemie, Institut für Biophysikalische Chemie 1090 Wien Austria
Inorg Chem Front. 2025 Jul 21. doi: 10.1039/d5qi01384d.
A strategy for the development of new vanadium-based drugs is the preparation of complexes that target proteins and bear molecules involved in the cellular metabolism as ligands, like α-hydroxycarboxylic acids. Based on these premises, this study explores the solution behaviour of the dioxidovanadium(V) complex of malic acid, Cs[V O(mal)]·2HO, and its interaction with the model protein lysozyme (HEWL) at room and at physiological temperature using V nuclear magnetic resonance (NMR), electrospray ionisation-mass spectrometry (ESI-MS) and X-ray crystallography. The results show the coexistence in aqueous solution of various molecular species containing two or ten V centres. In solution these species are formed regardless of the presence of HEWL, while at 37 °C the formation of [V O] (V) is precluded when the protein is present. Crystallographic data reveal that, when protein crystals are incubated with the V compound at room temperature (25 °C) and at pH 4.0, [VO], [V O(mal)], [V O] and [V O] are bound to the protein, while at 37 °C, under the same conditions, only [VO] interacts with HEWL. [V O] can bind the protein both covalently (as [V O] ion) and non-covalently. Whereas the transformation of [V O(mal)] to [V O(mal)] is expected on the basis of thermodynamic considerations, the formation of V and of the V-HEWL adduct is not easily predictable. Docking calculations confirm the experimental results and highlight the role of protein-protein interaction in the stabilization of the revealed adduct. This study demonstrates that vanadium compounds can undergo transformation in solution, giving rise to species that interact with proteins through several binding modes and stabilization mechanisms.
开发新型钒基药物的一种策略是制备以蛋白质为靶点、带有参与细胞代谢的分子作为配体的配合物，如α-羟基羧酸。基于这些前提，本研究利用钒核磁共振（NMR）、电喷雾电离质谱（ESI-MS）和X射线晶体学，探索了苹果酸二氧钒（V）配合物Cs[VO(mal)]·2H₂O在室温和生理温度下的溶液行为及其与模型蛋白溶菌酶（HEWL）的相互作用。结果表明，在水溶液中存在含有两个或十个钒中心的各种分子物种。在溶液中，这些物种的形成与HEWL的存在无关，而在37℃时，当蛋白质存在时，[VO₂]²⁺（V）的形成受到抑制。晶体学数据表明，当蛋白质晶体在室温（25℃）和pH 4.0条件下与钒化合物孵育时，[VO]²⁺、[VO(mal)]⁻、[VO₃]⁻和[VO₄]³⁻与蛋白质结合，而在37℃、相同条件下，只有[VO]²⁺与HEWL相互作用。[VO₂]²⁺可以通过共价（作为[VO₂]²⁺离子）和非共价方式与蛋白质结合。虽然基于热力学考虑，预计[VO(mal)]会转化为[VO(mal)]⁻，但V⁵⁺和V-HEWL加合物的形成并不容易预测。对接计算证实了实验结果，并突出了蛋白质-蛋白质相互作用在揭示的加合物稳定中的作用。本研究表明，钒化合物在溶液中会发生转化，产生通过多种结合模式和稳定机制与蛋白质相互作用的物种。
