Istituto di Biochimica e Biochimica Clinica, Università Cattolica del Sacro Cuore, Largo F. Vito 1, 00168 Rome, Italy.
Eur J Med Chem. 2012 Oct;56:145-54. doi: 10.1016/j.ejmech.2012.08.023. Epub 2012 Aug 24.
The anthracycline anticancer agents daunorubicin (DAUN) and doxorubicin (DOX) are reduced by different NADPH-dependent cytosolic reductases into their corresponding alcohol metabolites daunorubicinol (DAUNol) and doxorubicinol (DOXol), which have been implicated in the development of chronic cardiomyopathy. To better understand the individual importance of each enzyme in the reduction and to provide deeper insight into the binding at atomic level we performed molecular docking and dynamics simulations of DAUN and DOX into the active sites of human carbonyl reductase 1 (CBR1) and human aldehyde reductase (AKR1A1). Such simulations evidenced a different behavior between the reductases with respect to DAUN and DOX suggesting major contribution of CBR1 in the reduction. The results are in agreement with available experimental data and for each enzyme and anthracycline pair provided the identification of key residues involved in the interactions. The structural models that we have derived could serve as a useful tool for structure-guided drug design studies.
蒽环类抗癌药物柔红霉素（DAUN）和阿霉素（DOX）被不同的 NADPH 依赖性胞质还原酶还原为相应的醇代谢物柔红霉素醇（DAUNol）和阿霉素醇（DOXol），这与慢性心肌病的发展有关。为了更好地了解每种酶在还原中的个体重要性，并在原子水平上提供更深入的结合见解，我们对柔红霉素和阿霉素与人羰基还原酶 1（CBR1）和人醛还原酶（AKR1A1）的活性部位进行了分子对接和动力学模拟。这些模拟表明，两种还原酶对柔红霉素和阿霉素的行为不同，表明 CBR1 在还原中起主要作用。结果与现有实验数据一致，并为每种酶和蒽环类对提供了参与相互作用的关键残基的鉴定。我们得出的结构模型可以作为基于结构的药物设计研究的有用工具。
