title: A derivative of the natural compound kakuol affects DNA relaxation of topoisomerase IB inhibiting the cleavage reaction.
abstract: Topoisomerases IB are anticancer and antimicrobial targets whose inhibition by several natural and synthetic compounds has been documented over the last three decades. Here we show that kakuol, a natural compound isolated from the rhizomes of Asarum sieboldii, and a derivative analogue are able to inhibit the DNA relaxation mediated by the human enzyme. The analogue is the most efficient one and the inhibitory effect is enhanced upon pre-incubation with the enzyme. Analysis of the different steps of the catalytic cycle indicates that the inhibition occurs at the cleavage level and does not prevent DNA binding. Molecular docking shows that the compound preferentially binds near the active site at the bottom of the catalytic residue Tyr723, providing an atomistic explanation for its inhibitory activity.
authors.affiliation: University of Rome Tor Vergata, Department of Biology, Via Della Ricerca Scientifica, 00133 Rome, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Castelli
authors.forename: Sara
authors.initials: S
authors.lastname: Vieira
authors.forename: Ilda
authors.initials: I
authors.lastname: D'Annessa
authors.forename: Prafulla
authors.initials: P
authors.lastname: Katkar
authors.forename: Loana
authors.initials: L
authors.lastname: Musso
authors.forename: Sabrina
authors.initials: S
authors.lastname: Dallavalle
authors.forename: Alessandro
authors.initials: A
authors.lastname: Desideri
mesh_terms: D001483:Base Sequence; D052117:Benzodioxoles / Q000737:chemistry* / Q000494:pharmacology*; D001688:Biological Products / Q000737:chemistry* / Q000494:pharmacology*; D020134:Catalytic Domain; D004247:DNA / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D004264:DNA Topoisomerases, Type I / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D008958:Models, Molecular; D009690:Nucleic Acid Conformation / Q000187:drug effects*; D011427:Propiophenones / Q000737:chemistry* / Q000494:pharmacology*; D059004:Topoisomerase I Inhibitors / Q000737:chemistry / Q000494:pharmacology
chemical_list: C579139:2-hydroxy-4,5-methylenedioxypropiophenone; D052117:Benzodioxoles; D001688:Biological Products; D011427:Propiophenones; D059004:Topoisomerase I Inhibitors; D004247:DNA; D004264:DNA Topoisomerases, Type I; C528909:TOP1 protein, human