Molecular dynamics simulations of sulfone derivatives in complex with DNA topoisomerase IIα ATPase domain

Abstract

Human topoisomerase II alpha (TopoIIα) is a crucial enzyme involved in maintaining genomic integrity during the process of DNA replication and mitotic division. It is a vital therapeutic target for designing novel anticancer agents in targeted cancer therapy. Sulfones, members of organosulfur compounds, have been reported to possess various biological activities such as antimicrobial, anti-inflammatory, anti-HIV, anticancer, and antimalarial properties. In the present study, a series of sulfones was selected to evaluate their inhibitory activity against TopoIIα using computational approaches. Molecular docking results revealed that several sulfone analogs bind efficiently to the ATPase domain of TopoIIα. Among them, sulfones 18a, 60a, *4 b, *8 b, *3c, and 8c exhibit higher binding affinity than the known TopoII inhibitor, salvicine. Molecular dynamics simulations and free energy calculations based on MM/PB(GB)SA method demonstrated that sulfone *8 b strongly interacts with amino acid residues in the ATP-binding pocket (E87, N91, D94, I125, I141, F142, S149, G161, and A167), driven mainly by an electrostatic attraction and a strong H-bond formation at G161 residue. Altogether, the obtained results predicted that sulfones could have a high potential to be a lead molecule for targeting TopoIIα.

Communicated by Ramaswamy H. Sarma

Keywords:

• Human topoisomerase IIα
• sulfones
• anticancer agents
• MD simulations

Acknowledgements

The authors of the manuscript would like to thank the management of Chulalongkorn University (CU) for providing the facility and support to carry out this work. K.V. would also like to thank Ratchadapisek Somphot Fund for postdoctoral fellowship. Authors A. A., O. K., and C. K. would like to thank The Thailand Research Fund and the Center of Excellence for Innovation in Chemistry (BRG6180005), Ministry of Higher Education, Science, Research and Innovation. We also thank the Structural and Computational Biology Research Unit, Faculty of Science, CU, for facility and computing resources.

Disclosure statement

No potential conflict of interest was reported by the authors.

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Additional information

Funding

This work was financially supported by the Thailand Research Fund (grant number BRG6180005 and RSA6280085)