Computational Prediction Of Interaction Of Lumefantrine With Human Topoisomerase II Beta Complexed To DNA | 56678
Journal of Clinical Toxicology
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Lumefantrine (LF) is used in artemisinin-based combination therapies against malaria worldwide. It is genotoxic and
mutagenic to human lymphocytes in vitro and may interact non-covalently with DNA minor groove surface. Considering
that DNA binders are often topoisomerase inhibitors; in this study, we investigated the potential non-covalent interaction
of LF with human topoisomerase II beta (hTOP2β) complexed to DNA by molecular docking study. Computer-assisted
molecular analyses have been performed for predicting the possible interactions between hTOP2β-DNA complex and LF. The
hTOP2β-DNA complex bound to LF was then assessed for interactions, energetic contributions, and for identification of the
best correlation between the LF conformations and their associated scores. The fused-tricyclic 9H-fluorene rings in the LF
chemical structure promote the intercalative binding into cleaved DNA sites present in hTOP2β-DNA complex. Since this is a
polycyclic aromatic moiety, it gives the LF molecule the necessary planarity and aromaticity for intercalative binding to DNA
base pairs in the cleavage sites, which showed aromatic interactions of -8.6 kcal/mol in the binding computational analysis for
predicted binding affinity energy. The N-dibutyl moiety and hydroxyl group from LF accommodate into the major groove and
hydrogen bond to nitrogen and oxygen atoms on the base-pair in the DNA segment. The N-dibutyl moiety also interacts with
residues on the major groove side. The (4-chlorophenyl) methylidene moiety protrudes into the DNA minor groove side facing
nearby residues from this protein–DNA interface. The hypothesis on the interaction of LF with topoisomerase II needs to be
investigated using other approaches.
Carmen Lucia Bassi Branco has completed her PhD at São Paulo University in 2004 and Post-doctoral studies at the same university in 2007. She is Professor at the Federal University of Mato Grosso since 2009, where she develops research in the mutagenesis area.