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.
Highlights
Topoisomerases play a vital role in the maintenance of genomic integrity inside the cell by controlling DNA torsional stress [1]
In this paper we investigated the effect of MMV024937 on the catalytical cycle of Human DNA topoisomerase IB (htopIB) through experimental and computational approaches, and we tested its effect on
HtopIB plays essential roles in cell division by regulating all topological DNA stresses that arise during transcription or replication
Summary
Topoisomerases play a vital role in the maintenance of genomic integrity inside the cell by controlling DNA torsional stress [1]. This is accomplished by transiently breaking and rejoining DNA strands. Human DNA topoisomerase IB (htopIB) is one of six different topoisomerases that exist in humans [2]. HtopIB is a nuclear enzyme and, with type IA topoisomerase, belongs to the topoisomerase I subfamily that cuts only one DNA strand. DNA, whereas the type IB are attached to the 30 end during the catalytic cycle. Among topoisomerase families there are type II topoisomerases that cut both DNA strands [2]
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