Impact of Endothelial Cell Repair Mechanisms on Doxorubicin-Induced Cardiomyopathy: Exploring Molecular Docking and Simulation of Angiogenic Factors

Doxorubicin (Dox), despite being an effective anti-cancer drug, also causes cytotoxicity to non-cancerous tissues. ECs are highly abundant in the heart; thus, endothelial dysfunction is a major cause of doxorubicin-induced cardiomyopathy. The release of EPCs triggered by endothelial dysfunction, participates in the growth of new blood vessels and the repair of damaged endothelium to promote repair mechanism. The current study aimed to evaluate the effects of doxorubicin on SDF1/CXCR4 pathway via in silico molecular docking and simulation studies. Remarkably, heparin binding site of SDF1at LEU: 29 might be preoccupied by doxorubicin leads to poor expression because SDF1 activity heavily depends on its binding sites. On the other hand, active sites of CXCR4 at ASP: 171 and GLU: 288 also engaged by dox, leading to the assumption that doxorubicin restrict the receptor activity. Additionally, the interaction of doxorubicin at the proton acceptor site and ATP binding sites of VEGFR1, including ASP: 1022, GLY: 836, ALE: 837 and PHE: 838, suppresses the function of the receptor in the MAPK1/ERK2 and AKT1 signaling cascades. The co-expressing factor involved in SDF1/CXCR4 like VEGFR2, ANGPT1 and SHIP2 were also affected by specific amino acid interactions. This induces alterations in several vital biochemical pathways, leading to metabolic chaos. Taken together, we hypothesize that doxorubicin-mediated functional inactivity of SDF1 via its receptor CXCR4 and VEGFR1 impaired the cardiac EPCs regulation on angiogenesis and vascularization.