Computational Model of the Anthracycline-Binding Site in Carbonyl and Aldo-Keto Reductases: a Structural Basis for Designing Inhibitors
Thursday, June 22, 2006
Anthracycline antibiotics such as doxorubicin (DOX) and daunorubicin (DAU) are widely used antineoplastic agents in the treatment of various types of cancer. However their use is limited by the major side effect of cardiac toxicity which has not been effectively prevented by pharmacologic intervention with cardioprotective drugs. The mechanism by which DOX and DAU or their metabolites cause chronic cardiomyopathy is not fully understood.
Cytosolic reductases have been implicated in the development of anthracycline-induced cardiotoxicity. Carbonyl reductase 1 (CBR1) and aldo-keto reductases AKR1 are known to catalyze the reduction of DOX and DAU to the corresponding C13-hydroxyanthracycline.
It has been demostrated (Olson et al. Cancer Research, 2003, 63, 6602-6606) that a decrease in CBR1 would limit doxorubicin-induced toxicity.
Thus, diminution of CBR1 activity using pharmacologic inhibitors may be a useful means of ameliorating the side effects of doxorubicin in patients undergoing chemotherapy. Until now, no evidence has been provided for the spatial location of the DOX and DAU binding site in the carbonyl and aldo-keto reductases .
The aim of this work was therefore to investigate the interaction mechanism of the anthracyclineswith the cytosolic reductases. Predictive models have been constructed by means of a molecular docking study, that offer utility in guiding the rational design of inhibitors of reductase activity.