title: Biophysical and molecular docking studies of naphthoquinone derivatives on the ATPase domain of human topoisomerase II.
abstract: Numerous naphthoquinone derivatives, such as rhinacanthins function as anticancer drugs, which target hTopoII. The structure of hTopoII contains both an ATPase domain and a DNA binding domain. Several drugs bind to either one or both of these domains, thus modifying the activity of hTopoII. The naphthoquinone esters and amides used in this study showed that their hTopoIIα inhibitory activity was inversely proportional to ATP concentration. In order to better characterize the inhibitory action of these compounds, sufficient quantities of soluble functional hTopoII-ATPase domain were required. Therefore, both the alpha and beta isoforms of the hTopoII-ATPase domain were over-expressed in Escherichia coli. The hTopoIIα-ATPase activity was reduced in the presence of naphthoquinone derivatives. Additionally, a molecular docking study revealed that the selected naphthoquinone ester and amide bind to the ATP-binding domain of hTopoIIα. Collectively, the results here provide for the first time a novel insight into the interaction between naphthoquinone esters and amides, and the ATP-binding domain of hTopoIIα. The further elucidation of the mechanism of action of the naphthoquinone esters and amides inhibitory activity is essential.
authors.affiliation: Department of Biochemistry, Faculty of Science, Kasetsart University, 50, Phahon Yothin road, Chatuchak, 10900 Bangkok, Thailand. nonlawat.b@ku.ac.th
authors.forename: Nonlawat
authors.initials: N
authors.lastname: Boonyalai
authors.forename: Pichamon
authors.initials: P
authors.lastname: Sittikul
authors.forename: Narathip
authors.initials: N
authors.lastname: Pradidphol
authors.forename: Ngampong
authors.initials: N
authors.lastname: Kongkathip
mesh_terms: D000251:Adenosine Triphosphatases / Q000737:chemistry / Q000378:metabolism*; D000255:Adenosine Triphosphate / Q000378:metabolism; D000951:Antigens, Neoplasm / Q000737:chemistry / Q000378:metabolism; D004250:DNA Topoisomerases, Type II / Q000737:chemistry / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D004926:Escherichia coli / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D062105:Molecular Docking Simulation / Q000379:methods; D009285:Naphthoquinones / Q000737:chemistry / Q000493:pharmacokinetics*; D020033:Protein Isoforms / Q000378:metabolism; D017434:Protein Structure, Tertiary / Q000187:drug effects*; D059005:Topoisomerase II Inhibitors / Q000494:pharmacology*
chemical_list: D000951:Antigens, Neoplasm; D004268:DNA-Binding Proteins; D009285:Naphthoquinones; D020033:Protein Isoforms; D059005:Topoisomerase II Inhibitors; D000255:Adenosine Triphosphate; D000251:Adenosine Triphosphatases; D004250:DNA Topoisomerases, Type II