Carmen Lucia Bassi Branco
Federal University of Mato Grosso, Brazil
Title: Computational prediction of interaction of lumefantrine with human topoisomerase II beta complexed to DNA
Biography
Biography: Carmen Lucia Bassi Branco
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 oft en 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 identifi cation of the best correlation between the LF conformations and their associated scores. The fused-tricyclic 9H-fl uorene 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 affi nity energy. Th e 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. Th e (4-chlorophenyl) methylidene moiety protrudes into the DNA minor groove side facing nearby residues from this protein–DNA interface. Th e hypothesis on the interaction of LF with topoisomerase II needs to be investigated using other approaches.