AI Article Synopsis

  • - Human DNA topoisomerase IB plays a crucial role in managing supercoiled DNA through a cycle of cutting and rejoining DNA, essential for DNA functions.
  • - A drug from the Medicines for Malaria Venture was tested and found to strongly inhibit the enzyme's cleavage activity, negatively affecting the viability of various cancer cell lines.
  • - Molecular simulations revealed that the drug binds to the active site of the topoisomerase IB-DNA complex, suggesting its potential as a promising new treatment strategy for targeting this enzyme in cancer therapy.

Article 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.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8306514PMC
http://dx.doi.org/10.3390/ijms22147455DOI Listing

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