Dual targeting of CXC chemokine receptor 4 and multidrug resistance protein 1 by ZIN056 effectively combat daunorubicin resistance in acute myeloid leukemia cells.

Drug resistance, associated with the overexpression of CXC chemokine receptor CXCR4 and multidrug resistance protein 1 (MDR1) remains a significant barrier to effective therapy in Acute Myeloid Leukemia (AML). Targeting both CXCR4 and MDR1 could potentially enhance treatment efficacy in resistance. In silico computational screening of the Zinc natural product library using Discovery Studio Visualizer, Protein-Ligand Interaction Profiler, GROMACS, and GMX_MMPBSA techniques were used. THP-1, and SKM-1 cells were used for in vitro analysis. Flow cytometry was employed for target analysis and apoptosis enumerations. The virtual screening identified ZIN056 with favorable binding affinities of - 10.6 kcal/mol and - 9.1 kcal/mol for CXCR4 and MDR1, respectively. MD simulations demonstrated stable binding interactions, with Root Mean Square Deviation values around 0.2 nm for both proteins. The ΔG binding calculations further confirmed values of - 30.09 kcal/mol for CXCR4 and - 34.47 kcal/mol for MDR1, indicating energetically favorable binding. The compound inhibited the THP-1 and SKM-1 cell proliferation with GI