Understanding the binding of daunorubicin and doxorubicin to NADPH-dependent cytosolic reductases by computational methods

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.

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► A computational model of DOX and DAUN binding to cytosolic reductases is proposed.
► CBR1 is a more efficient enzyme in metabolizing anticancer anthracyclines.
► The computational model explains reported kinetic data.
► Anthracycline side chain in C9 has an important role in the substrate recognition.