TY - JOUR
T1 - Investigating the potential anticancer activities of antibiotics as topoisomerase II inhibitors and DNA intercalators
T2 - in vitro, molecular docking, molecular dynamics, and SAR studies
AU - Farouk, Faten
AU - Elmaaty, Ayman Abo
AU - Elkamhawy, Ahmed
AU - Tawfik, Haytham O.
AU - Alnajjar, Radwan
AU - Abourehab, Mohammed A.S.
AU - Saleh, Mohamed A.
AU - Eldehna, Wagdy M.
AU - Al‐Karmalawy, Ahmed A.
N1 - Publisher Copyright:
© 2023 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.
PY - 2023
Y1 - 2023
N2 - 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.Highlights Molecular 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.
AB - 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.Highlights Molecular 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.
KW - Antibiotics
KW - cytotoxicity
KW - MM-GBSA
KW - molecular docking and dynamics
KW - topoisomerase II
UR - http://www.scopus.com/inward/record.url?scp=85147046895&partnerID=8YFLogxK
U2 - 10.1080/14756366.2023.2171029
DO - 10.1080/14756366.2023.2171029
M3 - Article
C2 - 36701269
AN - SCOPUS:85147046895
SN - 1475-6366
VL - 38
JO - Journal of Enzyme Inhibition and Medicinal Chemistry
JF - Journal of Enzyme Inhibition and Medicinal Chemistry
IS - 1
M1 - 2171029
ER -