Molecular docking studies on thirteen fluoroquinolines with human topoisomerase II a and b

Abstract

DNA relaxation is an important step in DNA replication. DNA topoisomerases play a major role in DNA relaxation. Hence these enzymes are important targets for cancer drugs. DNA topoisomerase inhibitors bind to the transient enzyme-DNA complex and inhibit DNA replication. Various inhibitors of topoisomerase I and II are prescribed as drugs. Topoisomerase II is considered as an important target for the development of anticancer drugs. In this study we have demonstrated molecular docking of thirteen fluoroquinolines with human DNA topoisomerase II alpha (a) and beta (b). Fluoroquinolines are broad spectrum antibacterial antibiotics and it is highly effective against various bacterial infections. Some of the fluoroquinolines like moxifloxacin exert antifungal as well as anti-cancer activity. It forms complexes with topoisomerase II a and are responsible for stoppage DNA replication. Molecular docking studies showed that fluoroquinolines has shown formation of hydrogen bond and good binding affinity with human Topo2a and Topo2b. Hence FQs may inhibit the activity of enzyme topoisomerase by binding at its active site. Ofloxacin, sparafloxacin, ciprofloxacin and moxifloxacin are predicted to be the most potent inhibitors among the thirteen FQs docked. GLN773, ASN770, LYS723 and TRP931 amino acid residues of Topo2a are involved in binding with FQs while ASP479, SER480, ARG820, ARG503, LYS456 and GLN778 amino acid residues of Topo2b are involved in binding with FQs. Our in silico study suggests that fluoroquinolines could be repositioned as DNA topoisomerase II inhibitors hence can be used as anticancer drugs. In vitro and in vivo experiments need to be done to confirm their efficacy.

Keywords: Anticancer; Drug repositioning; Fluoroquinolines; Human DNA topoisomerase II; In silico; Molecular docking.

Fig. 1

Binding of ciprofloxacin with human topoisomerase II a

Fig. 2

Binding of enoxacin with human topoisomerase II a

Fig. 3

Binding of finafloxacin with human topoisomerase II a

Fig. 4

Binding of flumequine with human topoisomerase II a

Fig. 5

Binding of gatifloxacin with human topoisomerase II a

Fig. 6

Binding of levofloxacin with human topoisomerase II a

Fig. 7

Binding of lomefloxacin with human topoisomerase II a

Fig. 8

Binding of moxifloxacin with human topoisomerase II a

Fig. 9

Binding of norfloxacin with human topoisomerase II a

Fig. 10

Binding of ofloxacin with human topoisomerase II a

Fig. 11

Binding of prulifloxacin with human topoisomerase II a

Fig. 12

Binding of sarafloxacin with human topoisomerase II a

Fig. 13

Binding of sparafloxacin with human topoisomerase II a

Fig. 14

Binding of ciprofloxacin with human topoisomerase II b

Fig. 15

Binding of enoxacin with human topoisomerase II b

Fig. 16

Binding of finafloxacin with human topoisomerase II b

Fig. 17

Binding of flumefoxacin with human topoisomerase II b

Fig. 18

Binding of gatifloxacin with human topoisomerase II b

Fig. 19

Binding of levofloxacin with human topoisomerase II b

Fig. 20

Binding of lomefloxacin with human topoisomerase II b

Fig. 21

Binding of moxifloxacin with human topoisomerase II b

Fig. 22

Binding of norfloxacin with human topoisomerase II b

Fig. 23

Binding of prulifloxacin with human topoisomerase II b

Fig. 24

Binding of ofloxacin with human topoisomerase II b

Fig. 25

Binding of sarafloxacin with human topoisomerase II b

Fig. 26

Binding of sparafloxacin with human topoisomerase II b

Fig. 27

Binding of etoposide with human topoisomerase II a

Fig. 28

Binding of etoposide to human topoisomerase II b