Human DNA topoisomerase IB controls the topological state of supercoiled DNA through a complex catalytic cycle that consists of cleavage and religation reactions, allowing the progression of fundamental DNA metabolism. The catalytic steps of human DNA topoisomerase IB were analyzed in the presence of a drug, obtained by the open-access drug bank Medicines for Malaria Venture. The experiments indicate that the compound strongly and irreversibly inhibits the cleavage step of the enzyme reaction and reduces the cell viability of three different cancer cell lines. Molecular docking and molecular dynamics simulations suggest that the drug binds to the human DNA topoisomerase IB-DNA complex sitting inside the catalytic site of the enzyme, providing a molecular explanation for the cleavage-inhibition effect. For all these reasons, the aforementioned drug could be a possible lead compound for the development of an efficient anti-tumor molecule targeting human DNA topoisomerase IB.

Soren, B.c., Dasari, J.b., Ottaviani, A., Messina, B., Andreotti, G., Romeo, A., et al. (2021). In vitro and in silico characterization of an antimalarial compound with antitumor activity targeting human DNA topoisomerase IB. INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, 22(14), 7455 [10.3390/ijms22147455].

In vitro and in silico characterization of an antimalarial compound with antitumor activity targeting human DNA topoisomerase IB

Ottaviani A.;Romeo A.;Iacovelli F.;Falconi M.;Desideri A.;
2021-01-01

Abstract

Human DNA topoisomerase IB controls the topological state of supercoiled DNA through a complex catalytic cycle that consists of cleavage and religation reactions, allowing the progression of fundamental DNA metabolism. The catalytic steps of human DNA topoisomerase IB were analyzed in the presence of a drug, obtained by the open-access drug bank Medicines for Malaria Venture. The experiments indicate that the compound strongly and irreversibly inhibits the cleavage step of the enzyme reaction and reduces the cell viability of three different cancer cell lines. Molecular docking and molecular dynamics simulations suggest that the drug binds to the human DNA topoisomerase IB-DNA complex sitting inside the catalytic site of the enzyme, providing a molecular explanation for the cleavage-inhibition effect. For all these reasons, the aforementioned drug could be a possible lead compound for the development of an efficient anti-tumor molecule targeting human DNA topoisomerase IB.
2021
Pubblicato
Rilevanza internazionale
Articolo
Esperti anonimi
Settore BIO/11 - BIOLOGIA MOLECOLARE
English
cancer
drug
human DNA topoisomerase
molecular docking
Antimalarials
Antineoplastic Agents
Catalysis
Catalytic Domain
DNA
DNA Topoisomerases, Type I
Humans
In Vitro Techniques
Molecular Docking Simulation
Molecular Dynamics Simulation
Nucleic Acid Conformation
Protein Conformation
Topoisomerase I Inhibitors
Computer Simulation
Soren, B.c., Dasari, J.b., Ottaviani, A., Messina, B., Andreotti, G., Romeo, A., et al. (2021). In vitro and in silico characterization of an antimalarial compound with antitumor activity targeting human DNA topoisomerase IB. INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, 22(14), 7455 [10.3390/ijms22147455].
Soren, Bc; Dasari, Jb; Ottaviani, A; Messina, B; Andreotti, G; Romeo, A; Iacovelli, F; Falconi, M; Desideri, A; Fiorani, P
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2108/302487
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