Pradhan Amit Kumar, Shyam Abhijit, Mondal Paritosh
Department of Chemistry, Assam University, Silchar 788011, Assam, India.
ACS Omega. 2021 Oct 15;6(42):28084-28097. doi: 10.1021/acsomega.1c04168. eCollection 2021 Oct 26.
A comprehensive hydrolysis mechanism of the promising class of Au(III) anticancer drugs [Au(DMDT)Cl] (DMDT = ,-dimethyldithiocarbamate) () and [Au(damp)Cl] (damp = 2-[(dimethylamino)methyl]phenyl) (') was done by means of density functional theory (DFT) in combination with the CPCM solvation model to explore the solution behavior and stability under physiological conditions. The activation free energies (Δ) for the second hydrolysis, (13.7 kcal/mol) and ' (10.0 kcal/mol) are found to be relatively lower in comparison to the first hydrolysis, and their rate constant values are computed to be 5.62 × 10 and 2.90 × 10 s, respectively. Besides these, the interaction mechanisms of aquated and ' with the potential protein-binding sites cysteine (Cys) and selenocysteine (Sec) were also investigated in detail. The kinetic study and activation Gibbs free energy profiles reveal that the aquated complexes of and ' bind more effectively to the Se site of Sec than to the S site of Cys. Intra- and intermolecular hydrogen bonding play a pivotal role in stabilizing the intermediates and transition states involved in the ligand substitution reactions of and '. Natural population analysis (NPA) was done to determine the charge distributions on important atoms during the hydrolysis and ligand substitution reactions.
采用密度泛函理论（DFT）结合CPCM溶剂化模型，对有前景的一类金（III）抗癌药物[Au（DMDT）Cl]（DMDT = ，-二甲基二硫代氨基甲酸盐）（）和[Au（damp）Cl]（damp = 2-[(二甲氨基)甲基]苯基）（'）进行了全面的水解机理研究，以探索其在生理条件下的溶液行为和稳定性。发现第二次水解的活化自由能（Δ），（13.7 kcal/mol）和'（10.0 kcal/mol）与第一次水解相比相对较低，其速率常数分别计算为5.62×10和2.90×10 s。除此之外，还详细研究了水合的和'与潜在的蛋白质结合位点半胱氨酸（Cys）和硒代半胱氨酸（Sec）的相互作用机制。动力学研究和活化吉布斯自由能分布图表明，水合配合物和'与Sec的Se位点结合比与Cys的S位点结合更有效。分子内和分子间氢键在稳定和'的配体取代反应中涉及的中间体和过渡态方面起着关键作用。进行了自然布居分析（NPA）以确定水解和配体取代反应过程中重要原子上的电荷分布。
