Department of Chemistry Ugo Schiff, University of Florence, Sesto Fiorentino, Firenze, Italy.
Department of Chemical Sciences, University of Naples Federico II, Napoli, Italy.
Curr Top Med Chem. 2021;21(1):6-27. doi: 10.2174/1568026620666200624162213.
Pt-based drugs are widely used in clinics for the treatment of cancer. The mechanism of action of these molecules relies on their interaction with DNA. However, the recognition of these metal compounds by proteins plays an important role in defining pharmacokinetics, side effects and their overall pharmacological profiles. Single crystal X-ray diffraction studies provided important information on the molecular mechanisms at the basis of this process. Here, the molecular structures of representative adducts obtained upon reaction with proteins of selected Pt-based drugs, including cisplatin, carboplatin and oxaliplatin, are briefly described and comparatively examined. Data indicate that metal ligands play a significant role in driving the reaction of Pt compounds with proteins; non-covalent interactions that occur in the early steps of Pt compound/protein recognition process play a crucial role in defining the structure of the final Pt-protein adduct. In the metallated protein structures, Pt centers coordinate few protein side chains, such as His, Met, Cys, Asp, Glu and Lys residues upon releasing labile ligands.
基于铂的药物被广泛应用于癌症的临床治疗。这些分子的作用机制依赖于它们与 DNA 的相互作用。然而，这些金属化合物与蛋白质的识别在确定药代动力学、副作用及其整体药理学特征方面起着重要作用。单晶 X 射线衍射研究为这一过程的基础分子机制提供了重要信息。在这里，简要描述并比较了与选定的基于铂的药物（包括顺铂、卡铂和奥沙利铂）的蛋白质反应得到的代表性加合物的分子结构。数据表明，金属配体在驱动铂化合物与蛋白质反应方面起着重要作用；在铂化合物/蛋白质识别过程的早期步骤中发生的非共价相互作用在确定最终的铂-蛋白质加合物结构方面起着关键作用。在金属化蛋白质结构中，Pt 中心在释放不稳定配体后，仅与少量蛋白质侧链（如 His、Met、Cys、Asp、Glu 和 Lys 残基）配位。
