Daunorubicin (DNR) is a chemotherapeutic drug associated with multiple side effects, including drug resistance. As the molecular mechanism related to these side effects remain unclear and mostly hypothesized, this study addresses and compares the role of DNR and its metabolite Daunorubicinol (DAUNol) to induce apoptosis and drug resistance using molecular docking, Molecular Dynamics (MD) simulation, MM-PBSA and chemical pathway analysis. The results showed that DNR's interaction was stronger with Bax protein, Mcl-1:mNoxaB and Mcl-1:Bim protein complexes than DAUNol. On the other hand, contrasting results were obtained for drug resistance proteins where stronger interaction was obtained with DAUNol compared to DNR. Further, MD simulation performed for 100 ns provided the details of protein-ligand interaction. Most notable was the interaction of Bax protein with DNR, resulting in conformational changes at α-helices 5, 6 and 9, leading to Bax activation. Finally, the chemical signalling pathway analysis also revealed the regulation of different signalling pathways by DNR and DAUNol. It was observed that DNR majorly impacted the signalling associated with apoptosis while DAUNol mainly targeted pathways related to multidrug resistance and cardiotoxicity. Overall, the results highlight that DNR biotransformation reduces its capability to induce apoptosis while enhancing its ability to induce drug resistance and off-target toxicity.Communicated by Ramaswamy H. Sarma.
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