Force Fields, Quantum-Mechanical- and Molecular-Dynamics-Based Descriptors of Radiometal–Chelator

Radiopharmaceuticals are currently a key tool in cancer diagnosis and therapy. Metal-based radiopharmaceuticals are characterized by a radiometal–chelator moiety linked to a bio-vector that binds the biological target (e.g., a protein overexpressed in a particular tumor). The right match between radiometal and chelator influences the stability of the complex and the drug’s efficacy. Therefore, the coupling of the radioactive element to the correct chelator requires consideration of several features of the radiometal, such as its oxidation state, ionic radius, and coordination geometry. In this work, we systematically investigated about 120 radiometal–chelator complexes taken from the Cambridge Structural Database. We considered 25 radiometals and about 30 chelators, featuring both cyclic and acyclic geometries. We used quantum mechanics methods at the density functional theoretical level to generate the general AMBER force field parameters and to perform 1 µs-long all-atom molecular dynamics simulations in an explicit water solution. From these calculations, we extracted several key molecular descriptors accounting for both electronic- and dynamical-based properties. The whole workflow was carefully validated, and selected test-cases were investigated in detail. Molecular descriptors and force field parameters for the complexes considered in this study are made freely available, thus enabling their use in predictive models, molecular modelling, and molecular dynamics investigations of the interaction of compounds with macromolecular targets. Our work provides new insights in understanding the properties of radiometal–chelator complexes, with a direct impact for rational drug design of this important class of drugs.

放射性药物（Radiopharmaceuticals）目前是癌症诊断与治疗的关键工具。金属基放射性药物（Metal-based radiopharmaceuticals）的特征为带有与生物载体（bio-vector）相连的放射性金属-螯合基团（radiometal–chelator moiety），该生物载体可结合生物靶点（biological target），例如在特定肿瘤中过表达的蛋白。放射性金属与螯合剂的恰当匹配会影响配合物的稳定性与药物的疗效。因此，将放射性元素与合适的螯合剂进行耦联时，需考量放射性金属的多项特性，包括其氧化态、离子半径以及配位几何结构。本研究系统调研了取自剑桥结构数据库（Cambridge Structural Database）的约120种放射性金属-螯合配合物。本次研究选取了25种放射性金属与约30种螯合剂，其涵盖环状与非环状两种几何结构。我们采用密度泛函理论（density functional theory，DFT）层面的量子力学方法，生成通用AMBER力场（general AMBER force field）参数，并在显式水溶液（explicit water solution）中开展了时长为1微秒的全原子分子动力学模拟（all-atom molecular dynamics simulations）。通过上述计算，我们提取了多项关键分子描述符（molecular descriptors），涵盖电子特性与动力学特性两个维度。整个研究流程经过了严谨验证，并对选定的测试案例进行了详细探究。本研究涉及的配合物的分子描述符与力场参数已免费公开，可用于预测模型构建、分子建模以及化合物与大分子靶点相互作用的分子动力学研究。本研究为理解放射性金属-螯合配合物的特性提供了新视角，对该类重要药物的合理药物设计（rational drug design）具有直接的指导意义。