title: Virtual Screening for the Development of Dual-Inhibitors Targeting Topoisomerase IB and Tyrosyl-DNA Phosphodiesterase 1.
abstract: Human topoisomerase IB is an important target in cancer therapy and drugs selectively stabilizing the topoisomerase IB-DNA covalent complex are in clinical use for several cancer types. Tyrosyl- DNA phosphodiesterase 1 is involved in the DNA repair resolving the topoisomerase IB-DNA covalent complex that is extremely dangerous for the survival of the cells since it produces an irreversible DNA damage. Given the close biological relationship between these two enzymes, the development of synergistic inhibitors, called dual-inhibitors, is an important challenge in cancer therapy and computer-aided drug design may help in the identification of the best compounds. In this review, an overview of the compounds inhibiting one of the two enzymes or acting as dual inhibitors is provided. Moreover, the general procedures of the virtual screening approach, providing a description of two widely used opensource programs, namely AutoDock4 and AutoDock Vina, are described. Finally, an application of the two programs on a selected number of dual inhibitors for tyrosyl-DNA phosphodiesterase 1 and topoisomerase IB and their performance is briefly discussed.
authors.affiliation: Department of Biology, University of Rome Tor Vergata, Via della Ricerca Scientifica 1, 00133, Rome, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Cardamone
authors.affiliation: Department of Biology, University of Rome Tor Vergata, Via della Ricerca Scientifica 1, 00133, Rome, Italy.
authors.forename: Simone
authors.initials: S
authors.lastname: Pizzi
authors.affiliation: Interuniversity Consortium, National Institute Biostructure and Biosystem (INBB), Viale delle, Medaglie d'oro 305- 00136, Roma, Italy.
authors.forename: Federico
authors.initials: F
authors.lastname: Iacovelli
authors.affiliation: Interuniversity Consortium, National Institute Biostructure and Biosystem (INBB), Viale delle, Medaglie d'oro 305- 00136, Roma, Italy.
authors.forename: Mattia
authors.initials: M
authors.lastname: Falconi
authors.affiliation: Department of Biology, University of Rome Tor Vergata, Via della Ricerca Scientifica 1, 00133, Rome, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Desideri
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D003198:Computer Simulation; D017076:Computer-Aided Design; D004264:DNA Topoisomerases, Type I / Q000378:metabolism*; D004354:Drug Screening Assays, Antitumor / Q000379:methods*; D004357:Drug Synergism; D006801:Humans; D008958:Models, Molecular; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism*; D012984:Software
chemical_list: D000970:Antineoplastic Agents; D010727:Phosphoric Diester Hydrolases; C498508:TDP1 protein, human; D004264:DNA Topoisomerases, Type I; C528909:TOP1 protein, human
keywords: AutoDock4; autodock vina; dual-inhibitors; indenoisoquinolines; molecular docking; topoisomerase IB; tyrosyl-
  DNA phosphodiesterase; virtual screening.