Computational prediction of interaction of lumefantrine with human topoisomerase II beta complexed to DNA

7^th Euro-Global Summit on Toxicology & Applied Pharmacology

October 24-26, 2016 Rome, Italy

Carmen Lucia Bassi Branco

Federal University of Mato Grosso, Brazil

Scientific Tracks Abstracts: J Clin Toxicol

Abstract :

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 (hTOP2�²) complexed to DNA by molecular docking study. Computer-assisted molecular analyses have been performed for predicting the possible interactions between hTOP2�²-DNA complex and LF. The hTOP2�²-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 hTOP2�²-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 proteinâ��DNA interface. The hypothesis on the interaction of LF with topoisomerase II needs to be investigated using other approaches.

Biography :

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.

Email: [email protected]