Molecular recognition of naphthoquinone-containing compounds against human DNA topoisomerase IIα ATPase domain: A molecular modeling study

Abstract

© 2017 Elsevier B.V. Several quinone-based metabolites of anticancer drugs and naturally occurring quinone-containing compounds have been characterized as potent inhibitors toward topoisomerase IIα (TopoIIα), an essential enzyme involved in maintaining genomic integrity during DNA replication and mitotic division. Mansonone G (MG), a naphthoquinone-containing compound extracted from the heartwood of Mansonia gagei, exhibits various biological activities including antitumor potential. In the present study, MG and its semi-synthetic derivatives were selected to study the preferential binding site and dynamics behavior as well as to predict the inhibitory activity against TopoIIα using molecular modeling approaches. The molecular docking results revealed that the entire series of MG preferentially target to the ATPase domain. Among all studied MGs, the ester derivative MG14 containing C-10 length exhibited the highest binding affinity against TopoIIα and greater than that of the ATP-competitive inhibitor salvicine as well as 1,4-benzoquinone. Interestingly, the MG14 binding could induce the closed form of the turn region (residues 147–151) inside ATP-binding pocket, implying that this event might be one of the crucial mechanisms underlying TopoIIα inhibition. The obtained theoretical information is useful as rational guide for further development of new anticancer agents containing naphthoquinone moiety against TopoIIα.