Doxorubicin Disrupts the Calcium Homeostasis through its Antagonistic Activity on PINK1-An In-silico Approach
BIOINTERFACE RESEARCH IN APPLIED CHEMISTRY(2023)
Abstract
Doxorubicin (DOX) is an anthracycline antitumor drug, and though it is a widely used chemotherapeutic agent to treat various types of cancers, it induces irreversible dilated cardiomyopathy. In the face of many attempts, the molecular mechanism of doxorubicin-induced cardiotoxicity has not been entirely determined. On this note, we hypothesize that doxorubicin might dysregulate the calcium homeostasis through the electron transport chain (ETC). Therefore, we analyzed doxorubicin interaction with proteins involved in calcium homeostasis and electron transport chain by molecular docking. From our observation, we suggest that the doxorubicin strongly interacted with the protein of cardiolipin at their active binding site of Tyr63 with higher binding energies, while Tyr63 amino acid residue act as C3H1-type. and doxorubicin also interact with PINK1 and RYR2 at their active site. Thus, the significant binding of cardiolipin and PINK1 leads to the formation of oxidative stress, which increases ROS generation. An increased level of ROS activates RYR2 to release Ca2+ ions in mitochondria. Therefore, the interaction of doxorubicin with PINK1 is directly related to the accumulation of Ca2+ ions in the mitochondria by activating RYR2. Changes in the Ca2+ level of the mitochondria negatively affect the membrane potential (Delta psi), leading to dysfunction in cardiac contraction.
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Key words
Doxorubicin,calcium receptor channel,IP3R,RYR,SEIPIN,SERCA,Ubiquitin,Cardiolipin,PINK 1,cardiomyopathy
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