Abstract
Cytarabine, daunorubicin, doxorubicin and vincristine are clinically used for combinatorial therapies of cancers in different combinations. However, the knowledge about the interaction of these drugs with the metabolizing enzyme cytochrome P450 is limited. Therefore, we utilized computational methods to predict and assess the drug-binding modes. In this study, we performed docking, MD simulations and free energy landscape analysis to understand the drug-enzyme interactions, protein domain motions and the most populated free energy minimum conformations of the docked protein-drug complexes, respectively. The outcome of docking and MD simulations predicted the productive, as well as the non-productive binding modes of the selected drugs. Based on these interaction studies, we observed that S119, R212 and R372 are the major drug-binding residues in CYP3A4. The molecular mechanics Poisson–Boltzmann surface area analysis revealed the dominance of hydrophobic forces in the CYP3A4-drug association. Further analyses predicted the residues that may contain favorable drug-specific interactions. The probable binding modes of the cancer drugs from this study may extend the knowledge of the protein-drug interaction and pave the way to design analogs with reduced toxicity. In addition, they also provide valuable insights into the metabolism of the cancer drugs.
Highlights
Cytochrome P450 (CYPs) contributes to vital life processes by oxidizing compounds, such as drugs, chemicals, pollutants and xenobiotics [1,2]
The metabolic action of anticancer drugs cytarabine, daunorubicin and doxorubicin by CYP3A4 is not completely understood to date, whereas the metabolic products have been reported for vincristine [10]
The detailed binding orientation, as well as the interaction profiles would be essential in understanding the metabolism of these drugs
Summary
Cytochrome P450 (CYPs) contributes to vital life processes by oxidizing compounds, such as drugs, chemicals, pollutants and xenobiotics [1,2]. CYPs are major drug-metabolizing enzymes that play an important role in the oxidative metabolism of the predominantly-used clinical drugs. Among the CYPs isoforms, the CYP3A4 enzyme metabolizes approximately half of the drugs. CYP3A4 has a high level of expression in the liver and broad capacity to oxidize structurally-diverse substrates due to its large active site cavity [3,4]. CYP3A4 has diverse substrate specificity and co-operative substrate binding, which often leads to unacceptable drug-drug interactions, as well as toxic side effects [5]. CYP3A4 can lower the bioavailability and therapeutic efficiency of pharmaceuticals through fast degradation, whereas drug plasma levels can be increased if CYP3A4 is inhibited [6]
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