The Use of Methods of Computer-Aided Drug Discovery in the Development of Topoisomerase II Inhibitors: Applications and Future Directions

DNA TopoisomeraseII (TopoII) is a key enzyme for gene transcription, DNA replication and chromosomal segregation that are essential for cellular metabolism and cell division. Cancer cells often hijack these TopoII activities for tumor development and progression, rationalizing TopoII inhibition to be an effective anticancer therapy and evidenced by the fact that there are several TopoII inhibitors including etoposide and doxorubicin broadly used as chemotherapies in clinics. However, these therapeutics tend to cause severe side effects and suffer from relatively low ligand affinity, leaving TopoII targeting with new small molecules an active area of research. In recent years, computer-aided drug discovery (CADD) approaches have been actively applied to expand our knowledge on the role of TopoII in cancer and to develop novel strategies to block its activities. Herein, we review the studies that employed structure-based approaches such as docking and molecular dynamic simulations, as well as ligand-based approaches such as QSAR (quantitative-structure activity relationship) modelling among others, to enhance our understanding on the existing drugs targeting TopoII and to further explore the opportunities for novel drug candidates.