scholarly journals In Vitro and In Silico Characterization of an Antimalarial Compound with Antitumor Activity Targeting Human DNA Topoisomerase IB

2021 ◽  
Vol 22 (14) ◽  
pp. 7455
Author(s):  
Bini Chhetri Soren ◽  
Jagadish Babu Dasari ◽  
Alessio Ottaviani ◽  
Beatrice Messina ◽  
Giada Andreotti ◽  
...  
Keyword(s):  
Enzyme Reaction ◽  
Dna Topoisomerase ◽  
Human Dna ◽  
Topoisomerase Ib ◽  
Topological State ◽  
Cleavage Step ◽  
Dynamics Simulations ◽  
In Silico Characterization ◽  
Dna Complex

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.

Comparative studies of oxindolimine-metal complexes as inhibitors of human DNA topoisomerase IB

2018 ◽  
Vol 186 ◽  
pp. 85-94 ◽  
Author(s):  
Silvia Castelli ◽  
Marcos Brown Gonçalves ◽  
Prafulla Katkar ◽  
Gabriela Cristina Stuchi ◽  
Ricardo Alexandre Alves Couto ◽  
...  
Keyword(s):  
Metal Complexes ◽  
Comparative Studies ◽  
Dna Topoisomerase ◽  
Human Dna ◽  
Topoisomerase Ib

Synthesis, crystal structure, DNA interaction and in vitro anticancer activity of a Cu(ii) complex of purpurin: dual poison for human DNA topoisomerase I and II

RSC Advances ◽  
2014 ◽  
Vol 4 (103) ◽  
pp. 59344-59357 ◽  
Author(s):  
Piyal Das ◽  
Chetan Kumar Jain ◽  
Sanjoy K. Dey ◽  
Rajat Saha ◽  
Abhishek Dutta Chowdhury ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Topoisomerase I ◽  
Dna Interaction ◽  
Dna Topoisomerase I ◽  
Oxygen Species ◽  
Dna Topoisomerase ◽  
Human Dna ◽  
Anti Tumor Activity ◽  
Human Dna Topoisomerase I

Although generation of reactive oxygen species (ROS) by anthracycline anticancer drugs is essential for anti-tumor activity, they make these drugs cardiotoxic.

Bioassays and In Silico Methods in the Identification of Human DNA Topoisomerase IIα Inhibitors

2018 ◽  
Vol 25 (28) ◽  
pp. 3286-3318 ◽  
Author(s):  
Kaja Bergant ◽  
Matej Janezic ◽  
Andrej Perdih
Keyword(s):  
In Silico ◽  
In Vivo Studies ◽  
Topoisomerase Iiα ◽  
Dna Topoisomerase ◽  
Human Dna ◽  
Practical Guidelines ◽  
In Silico Methods ◽  
Dna Topoisomerase Iiα

Background: The family of DNA topoisomerases comprises a group of enzymes that catalyse the induction of topological changes to DNA. These enzymes play a role in the cell replication machinery and are, therefore, important targets for anticancer drugs - with human DNA topoisomerase IIα being one of the most prominent. Active compounds targeting this enzyme are classified into two groups with diverse mechanisms of action: DNA poisons act by stabilizing a covalent cleavage complex between DNA and the topoisomerase enzyme, transforming it into a cellular toxin, while the second diverse group of catalytic inhibitors, provides novel inhibition avenues for tackling this enzyme due to frequent occurrence of side effects observed during the DNA poison therapy. Methods: Based on a comprehensive literature search we present an overview of available bioassays and in silico methods in the identification of human DNA topoisomerase IIα inhibitors. Results and Conclusion: A comprehensive outline of the available methods and approaches that explore in detail the in vitro mechanistic and functional aspects of the topoisomerase IIα inhibition of both topo IIα inhibitor groups is presented. The utilized in vitro cell-based assays and in vivo studies to further explore the validated topo IIα inhibitors in subsequent preclinical stages of the drug discovery are discussed. The potential of in silico methods in topoisomerase IIα inhibitor discovery is outlined. A list of practical guidelines was compiled to aid new as well experienced researchers in how to optimally approach the design of targeted inhibitors and validation in the preclinical drug development stages.

scholarly journals Dynamics of human DNA topoisomerases IIα and IIβ in living cells

2002 ◽  
Vol 157 (1) ◽  
pp. 31-44 ◽  
Author(s):  
Morten O. Christensen ◽  
Morten K. Larsen ◽  
Hans Ullrich Barthelmes ◽  
Robert Hock ◽  
Claus L. Andersen ◽  
...  
Keyword(s):  
Structural Component ◽  
Mitotic Chromosome ◽  
Proliferating Cells ◽  
Dna Topoisomerase ◽  
Genomic Changes ◽  
Human Dna ◽  
Catalytic Dna ◽  
Topo Ii ◽  
Chromosome Scaffold

DNA topoisomerase (topo) II catalyses topological genomic changes essential for many DNA metabolic processes. It is also regarded as a structural component of the nuclear matrix in interphase and the mitotic chromosome scaffold. Mammals have two isoforms (α and β) with similar properties in vitro. Here, we investigated their properties in living and proliferating cells, stably expressing biofluorescent chimera of the human isozymes. Topo IIα and IIβ behaved similarly in interphase but differently in mitosis, where only topo IIα was chromosome associated to a major part. During interphase, both isozymes joined in nucleolar reassembly and accumulated in nucleoli, which seemed not to involve catalytic DNA turnover because treatment with teniposide (stabilizing covalent catalytic DNA intermediates of topo II) relocated the bulk of the enzymes from the nucleoli to nucleoplasmic granules. Photobleaching revealed that the entire complement of both isozymes was completely mobile and free to exchange between nuclear subcompartments in interphase. In chromosomes, topo IIα was also completely mobile and had a uniform distribution. However, hypotonic cell lysis triggered an axial pattern. These observations suggest that topo II is not an immobile, structural component of the chromosomal scaffold or the interphase karyoskeleton, but rather a dynamic interaction partner of such structures.

scholarly journals Human DNA topoisomerase I-mediated cleavage and recombination of duck hepatitis B virus DNA in vitro

1999 ◽  
Vol 27 (8) ◽  
pp. 1919-1925 ◽  
Author(s):  
P. Pourquier ◽  
Y. Pommier ◽  
A. D. Jensen ◽  
S. S. Gong ◽  
C. E. Rogler
Keyword(s):  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Topoisomerase I ◽  
Dna Topoisomerase I ◽  
Dna Topoisomerase ◽  
Duck Hepatitis ◽  
Human Dna ◽  
B Virus ◽  
Human Dna Topoisomerase I

Molecular modelling studies on the interactions of human DNA topoisomerase IB with pyridoxal-compounds

Biochimie ◽  
2007 ◽  
Vol 89 (4) ◽  
pp. 468-473 ◽  
Author(s):  
Serge Christmann-Franck ◽  
Serge Fermandjian ◽  
Gilles Mirambeau ◽  
P. Arsène Der Garabedian
Keyword(s):  
Molecular Modelling ◽  
Dna Topoisomerase ◽  
Human Dna ◽  
Topoisomerase Ib ◽  
Molecular Modelling Studies ◽  
Modelling Studies

scholarly journals In vitro and in silico characterization of adiponectin-receptor agonist dipeptides

2021 ◽  
Vol 5 (1) ◽  
Author(s):  
Yuna Lee ◽  
Akihiro Nakano ◽  
Saya Nakamura ◽  
Kenta Sakai ◽  
Mitsuru Tanaka ◽  
...  
Keyword(s):  
Glucose Uptake ◽  
Glucose Transporter ◽  
Adenosine Monophosphate ◽  
Adiponectin Receptor ◽  
L6 Myotubes ◽  
Glut4 Expression ◽  
Binding Pockets ◽  
Dynamics Simulations ◽  
In Silico Characterization

AbstractThe aim of this study is to develop a dipeptide showing an adiponectin receptor 1 (AdipoR1) agonistic effect in skeletal muscle L6 myotubes. Based on the structure of the AdipoR1 agonist, AdipoRon, 15 synthetic dipeptides were targeted to promote glucose uptake in L6 myotubes. Tyr-Pro showed a significant increase in glucose uptake among the dipeptides, while other dipeptides, including Pro-Tyr, failed to exert this effect. Tyr-Pro induces glucose transporter 4 (Glut4) expression in the plasma membrane, along with adenosine monophosphate-activated protein kinase (AMPK) activation. In AdipoR1-knocked down cells, the promotion by Tyr-Pro was ameliorated, indicating that Tyr-Pro may directly interact with AdipoR1 as an agonist, followed by the activation of AMPK/Glut4 translocation in L6 myotubes. Molecular dynamics simulations revealed that a Tyr-Pro molecule was stably positioned in the two potential binding pockets (sites 1 and 2) of the seven-transmembrane receptor, AdipoR1, anchored in a virtual 1-palmitoyl-2-oleoyl-phosphatidylcholine membrane. In conclusion, we demonstrated the antidiabetic function of the Tyr-Pro dipeptide as a possible AdipoR1 agonist.

scholarly journals A single mutation in the 729 residue modulates human DNA topoisomerase IB DNA binding and drug resistance

2008 ◽  
Vol 36 (17) ◽  
pp. 5635-5644 ◽  
Author(s):  
Carmen Losasso ◽  
Erica Cretaio ◽  
Paola Fiorani ◽  
Ilda D’Annessa ◽  
Giovanni Chillemi ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Dna Binding ◽  
Single Mutation ◽  
Dna Topoisomerase ◽  
Human Dna ◽  
Topoisomerase Ib
Sign in / Sign up

Export Citation Format

Share Document