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. 2023 Dec;38(1):2171029.
doi: 10.1080/14756366.2023.2171029.

Investigating the potential anticancer activities of antibiotics as topoisomerase II inhibitors and DNA intercalators: in vitro, molecular docking, molecular dynamics, and SAR studies

Faten Farouk  1 , Ayman Abo Elmaaty  2 , Ahmed Elkamhawy  3   4 , Haytham O Tawfik  5 , Radwan Alnajjar  6   7   8 , Mohammed A S Abourehab  9 , Mohamed A Saleh  10   11 , Wagdy M Eldehna  12   13 , Ahmed A Al-Karmalawy  1
Affiliations

Investigating the potential anticancer activities of antibiotics as topoisomerase II inhibitors and DNA intercalators: in vitro, molecular docking, molecular dynamics, and SAR studies

Faten Farouk et al. J Enzyme Inhib Med Chem. 2023 Dec.

Abstract

Topoisomerase II (TOP-2) is a promising molecular target for cancer therapy. Numerous antibiotics could interact with biologically relevant macromolecules and provoke antitumor potential. Herein, molecular docking studies were used to investigate the binding interactions of 138 antibiotics against the human topoisomerase II-DNA complex. Followed by the MD simulations for 200 ns and MM-GBSA calculations. On the other hand, the antitumor activities of the most promising candidates were investigated against three cancer cell lines using doxorubicin (DOX) as a reference drug. Notably, spiramycin (SP) and clarithromycin (CL) showed promising anticancer potentials on the MCF-7 cell line. Moreover, azithromycin (AZ) and CL exhibited good anticancer potentials against the HCT-116 cell line. Finally, the TOP-2 enzyme inhibition assay was carried out to confirm the proposed rationale. Briefly, potent TOP-2 inhibitory potentials were recorded for erythromycin (ER) and roxithromycin (RO). Additionally, a SAR study opened eyes to promising anticancer pharmacophores encountered by these antibiotics.HighlightsMolecular docking studies of 139 antibiotics against the topoisomerase II-DNA complex.SP, RO, AZ, CL, and ER were the most promising and commercially available candidates.Molecular dynamics simulations for 200 ns for the most promising five complexes.MM-GBSA calculations for the frontier five complexes.SP and CL showed promising anticancer potentials on the MCF-7 cell line, besides, AZ and CL exhibited good anticancer potentials against the HCT-116 cell line.Potent TOP-2 inhibitory potentials were recorded for ER and RO.

Keywords: Antibiotics; MM-GBSA; cytotoxicity; molecular docking and dynamics; topoisomerase II.

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Conflict of interest statement

The authors report no conflicts of interest.

Figures

None
Graphical abstract
Figure 1.
Figure 1.
Some previously reported topoisomerase II inhibitors and DNA intercalators display their pharmacophoric characteristics.
Figure 2.
Figure 2.
The 2D (A) and 3D (B) illustrations display the superimposition of the native co-crystallised EVP and redocked one (Mauve and Light Blue, respectively, in 3D picture) at the topoisomerase II-DNA complex (PDB entry: 3QX3) with RMSD value 1.42 Å.
Figure 3.
Figure 3.
2D (A) and 3D (B) illustrations revealing the binding interactions of the re-docked co-crystallised ligand (EVP) at the topoisomerase II-DNA complex active site, where red dashed lines stand for H-bonds, and black ones stand for H-pi bonds.
Figure 4.
Figure 4.
The 2D and 3D binding interactions of compounds AZ (A,B), CL (C,D), and ER (E,F) reveal their binding interactions at the topoisomerase II-DNA complex active site.
Figure 5.
Figure 5.
The 2D and 3D binding interactions of compounds RO (A,B), and SP (C,D) reveal their binding interactions at the topoisomerase II-DNA complex active site (PDB: 3QX3).
Figure 6.
Figure 6.
The RMSD of the six complexes (SP, RO, AZ, CL, and ER) within the topoisomerase II-DNA complex compared to the co-crystallised (EVP) inhibitor as a function of simulation time (200 ns).
Figure 7.
Figure 7.
The RMSD of the ligands (SP, RO, AZ, CL, and ER) within the topoisomerase II-DNA complex compared to the co-crystallised (EVP) inhibitor as a function of simulation time (200 ns).
Figure 8.
Figure 8.
Histograms indicating the fractions of binding between the protein’s amino acids and its ligand for (A) SP-3QX3, (B) RO-3QX3, (C) AZ-3QX3, (D) CL-3QX3, (E) ER-3QX3, and (F) EVP-3QX3 complexes.
Figure 9.
Figure 9.
(A) Heat map describing the protein–ligand interactions regarding the simulation time of 200 ns for SP-3QX3. (B) Heat map describing the protein–ligand interactions regarding the simulation time of 200 ns for RO-3QX3.
Figure 9.
Figure 9.
(A) Heat map describing the protein–ligand interactions regarding the simulation time of 200 ns for SP-3QX3. (B) Heat map describing the protein–ligand interactions regarding the simulation time of 200 ns for RO-3QX3.
Figure 10.
Figure 10.
Inhibitory potential (IC50) of the most promising and commercially available antibiotics (SP, RO, AZ, CL, and ER) against MCF-7, HepG2, and HCT-116.
Figure 11.
Figure 11.
(A) The measured IC50 of tested antibiotics (SP, RO, AZ, CL, and ER) on TOP-2 compared to DOX. (B) Gel electrophoresis image representing the variable decatenation potential of DNA by TOP-2 as inhibited by DOX and the tested antibiotics (SP, RO, AZ, CL, and ER). The N Lane represents no TOP-2 activity while the P lane is the uninhibited enzyme.
Figure 12.
Figure 12.
SAR study for the affinity of the examined 138 antibiotics as topoisomerase II inhibitors and DNA intercalators.
See this image and copyright information in PMC

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