We present a computational strategy based on thermodynamic cycles to predict and describe the chemical equilibrium between the 3d-transition metal ions Zn²⁺, Cu²⁺, and VO²⁺ and the widely used antineoplastic drug doxorubicin. Our method involves benchmarking a theoretical protocol to compute gas-phase quantities using DLPNO Coupled-Cluster calculations as reference, followed by estimating solvation contributions to the reaction Gibbs free energies using both explicit partial (micro)solvation steps for charged solutes and neutral coordination complexes, as well as a continuum solvation procedure for all solutes involved in the complexation process. We rationalized the stability of these doxorubicin-metal complexes by inspecting quantities obtained from the topology of their electron densities, particularly the bond critical points and non-covalent interaction index. Our approach allowed us to identify representative species in solution phase, infer the most likely complexation process for each case, and identify key intramolecular interactions involved in the stability of these compounds. To the best of our knowledge, this is the first study reporting thermodynamic constants for the complexation of doxorubicin with transition metal ions. Unlike other methods, our procedure is computationally affordable for medium-sized systems and provides valuable insights even with limited experimental data. Furthermore, it can be extended to describe the complexation process between 3d-transition metal ions and other bioactive ligands.

我们提出了一种基于热力学循环的计算策略来预测和描述 3d过渡金属离子 Zn ²⁺、Cu ²⁺和 VO ^{2+之间的化学平衡}以及广泛使用的抗肿瘤药物阿霉素。我们的方法包括使用 DLPNO 耦合簇计算作为参考来对计算气相量的理论协议进行基准测试，然后使用带电溶质和中性配位络合物的显式部分（微）溶剂化步骤来估计溶剂化对反应吉布斯自由能的贡献，以及络合过程中涉及的所有溶质的连续溶剂化程序。我们通过检查从电子密度拓扑中获得的量，特别是键临界点和非共价相互作用指数，合理化了这些阿霉素-金属配合物的稳定性。我们的方法使我们能够识别溶液相中的代表性物种，推断每种情况最可能的络合过程，并确定与这些化合物稳定性有关的关键分子内相互作用。据我们所知，这是第一项报告阿霉素与过渡金属离子络合热力学常数的研究。与其他方法不同，我们的程序在计算上对于中型系统来说是负担得起的，并且即使在实验数据有限的情况下也能提供有价值的见解。此外，它可以扩展到描述 3 之间的络合过程 我们的程序在计算上对于中型系统来说是负担得起的，即使实验数据有限，也能提供有价值的见解。此外，它可以扩展到描述 3 之间的络合过程 我们的程序在计算上对于中型系统来说是负担得起的，即使实验数据有限，也能提供有价值的见解。此外，它可以扩展到描述 3 之间的络合过程d-过渡金属离子和其他生物活性配体。