Structural basis of DNA topoisomerase II-α (Top2-α) inhibition: a computational analysis of interactions between Top2-α and its inhibitors

Farsani, Farzaneh Mohamadi; Ganjalikhany, Mohamad Reza; Dehbashi, Moein; Naeini, Marjan Mojtabavi; Vallian, Sadeq

doi:10.1007/s00044-016-1567-1

Cited by 9 publications

(5 citation statements)

References 42 publications

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“…Several computational techniques such as docking and molecular dynamics simulation were used in this study. These techniques could clearly explain every molecular details from conformational changes during enzyme activity to molecular binding phenomena in an enzyme-ligand system at atomic level 21–26 . We have performed an intensive structural investigation for the understanding of dynamics and conformational motions occurred in LDHA.…”

Section: Introductionmentioning

confidence: 99%

Novel Peptide Inhibitors for Lactate Dehydrogenase A (LDHA): A Survey to Inhibit LDHA Activity via Disruption of Protein-Protein Interaction

Jafary

Ganjalikhany

Hemati

et al. 2019

Sci Rep

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Lactate dehydrogenase A (LDHA) is a critical metabolic enzyme belonging to a family of 2-hydroxy acid oxidoreductases that plays a key role in anaerobic metabolism in the cells. In hypoxia condition, the overexpression of LDHA shifts the metabolic pathway of ATP synthesis from oxidative phosphorylation to aerobic glycolysis and the hypoxia condition is a common phenomenon occurred in the microenvironment of tumor cells; therefore, the inhibition of LDHA is considered to be an excellent strategy for cancer therapy. In this study, we employed in silico methods to design inhibitory peptides for lactate dehydrogenase through the disturbance in tetramerization of the enzyme. Using peptide as an anti-cancer agent is a novel approach for cancer therapy possessing some advantages with respect to the chemotherapeutic drugs such as low toxicity, ease of synthesis, and high target specificity. So peptides can act as appropriate enzyme inhibitor in parallel to chemical compounds. In this study, several computational techniques such as molecular dynamics (MD) simulation, docking and MM-PBSA calculation have been employed to investigate the structural characteristics of the monomer, dimer, and tetramer forms of the enzyme. Analysis of MD simulation and protein-protein interaction showed that the N-terminal arms of each subunit have an important role in enzyme tetramerization to establish active form of the enzyme. Hence, N-terminal arm can be used as a template for peptide design. Then, peptides were designed and evaluated to obtain best binders based on the affinity and physicochemical properties. Finally, the inhibitory effect of the peptides on subunit association was measured by dynamic light scattering (DLS) technique. Our results showed that the designed peptides which mimic the N-terminal arm of the enzyme can successfully target the C-terminal domain and interrupt the bona fide form of the enzyme subunits. The result of this study makes a new avenue to disrupt the assembly process and thereby oppress the function of the LDHA.

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Section: Introductionmentioning

confidence: 99%

Novel Peptide Inhibitors for Lactate Dehydrogenase A (LDHA): A Survey to Inhibit LDHA Activity via Disruption of Protein-Protein Interaction

Jafary

Ganjalikhany

Hemati

et al. 2019

Sci Rep

Self Cite

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“…Ciprofloxacin binds to the catalytic Mg 2+ ion used for re-ligation of DNA via turnover of phosphotyrosine to tyrosine, 48 whereas the mitoxantrone interactions are facilitated by non-covalent contacts unique to TopIIα. 49 This could result in mitoxantrone acting in the bacteria as an intercalator, which would explain the similarity in filament distribution with DNA damaging agents.…”

Section: Resultsmentioning

confidence: 99%

A monoadduct generating Ru(ii) complex induces ribosome biogenesis stress and is a molecular mimic of phenanthriplatin

et al. 2023

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“…Herein, it is possible to speculate that the use of methods of CADD modeling could generally be used to optimize numerous known TopoII poisons and catalytic inhibitors into isoform specific agents. For example, Farsani et al employed docking to gain insights into TopoIIβ interactions with mitoxantrone and amsacrine, , where authors identified key residues involved in ligand binding and outlined differences in binding of the two isoforms.…”

Section: The State Of the Artmentioning

confidence: 99%

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

Radaeva

Dong

Cherkasov

2020

J. Chem. Inf. Model.

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Topoisomerase II (TopoII) is an enzyme essential for cellular metabolism and replication as it regulates DNA topology. Since inhibition of TopoII induces cell death, it is a wellestablished drug target in cancer therapy; several broadly used anticancer drugs including etoposide and doxorubicin are TopoII inhibitors. However, these therapeutics tend to cause severe side effects and suffer from relatively low ligand affinity, leaving TopoII targeting with small molecules an active area of research. In recent years computer-aided drug discovery (CADD) approaches have been actively used to expand knowledge on the role of TopoII in cancer and to develop novel strategies for its inhibition. Herein, we overview studies that employed structurebased approaches such as docking and molecular dynamic simulations, as well as ligand-based approaches, such as QSAR (quantitative structure−activity relationship) modeling among others, to gain understanding in TopoII targeting with existing drugs and to search for novel drug candidates.

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Structural basis of DNA topoisomerase II-α (Top2-α) inhibition: a computational analysis of interactions between Top2-α and its inhibitors

Cited by 9 publications

References 42 publications

Novel Peptide Inhibitors for Lactate Dehydrogenase A (LDHA): A Survey to Inhibit LDHA Activity via Disruption of Protein-Protein Interaction

Novel Peptide Inhibitors for Lactate Dehydrogenase A (LDHA): A Survey to Inhibit LDHA Activity via Disruption of Protein-Protein Interaction

A monoadduct generating Ru(ii) complex induces ribosome biogenesis stress and is a molecular mimic of phenanthriplatin

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

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