title: Structure-based virtual screening toward the discovery of novel inhibitors of the DNA repair activity of the human apurinic/apyrimidinic endonuclease 1.
abstract: The DNA repair activity of human apurinic/apyrimidinic endonuclease 1 (APE1) has been recognized as a promising target for the development of small-molecule inhibitors to be used in combination with anticancer agents. In an attempt to identify novel inhibitors of APE1, we present a structure-based virtual screening (SBVS) study based on molecular docking analysis of the compounds of NCI database using the GOLD 5.1.0 (Genetic Optimization for Ligand Docking) suite of programs. Compounds selected in this screening were tested with a fluorescence-based APE1 endonuclease activity assay. Two compounds (37 and 41) were able to inhibit the multifunctional enzyme APE1 in the micromolar range, while compound 22 showed inhibitory effects at nanomolar concentrations. These results were confirmed by a plasmid DNA nicking assay. In addition, the potential APE1 inhibitors did not affect the cell viability of non-tumor MCF10A cells. Overall, compounds 22, 37, and 41 appear to be important scaffolds for the design of novel APE1 inhibitors and this study highlights the relevance of in silico-based approaches as valuable tools in drug discovery.
authors.affiliation: Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal.
authors.forename: Patrícia S
authors.initials: PS
authors.lastname: Guerreiro
authors.affiliation: BioISI - Biosystems and Integrative Sciences Institute, Faculdade de Ciências, Universidade de Lisboa, Lisbon, Portugal.
authors.forename: Sílvia G
authors.initials: SG
authors.lastname: Estácio
authors.affiliation: Departamento de Química e Bioquímica and Centro de Química e Bioquímica, Faculdade de Ciências, Universidade de Lisboa, Lisbon, Portugal.
authors.forename: Fernando
authors.initials: F
authors.lastname: Antunes
authors.affiliation: Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal.|CBIOS, Universidade Lusófona Research Center for Biosciences and Health Technologies, Lisbon, Portugal.
authors.forename: Ana S
authors.initials: AS
authors.lastname: Fernandes
authors.affiliation: Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal.|Centro de Química Estrutural (CQE), Instituto Superior Técnico, Universidade de Lisboa, Lisbon, Portugal.
authors.forename: Pedro F
authors.initials: PF
authors.lastname: Pinheiro
authors.affiliation: Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal.|CBIOS, Universidade Lusófona Research Center for Biosciences and Health Technologies, Lisbon, Portugal.
authors.forename: João G
authors.initials: JG
authors.lastname: Costa
authors.affiliation: Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal.
authors.forename: Matilde
authors.initials: M
authors.lastname: Castro
authors.affiliation: Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal.
authors.forename: Joana P
authors.initials: JP
authors.lastname: Miranda
authors.affiliation: Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal. rguedes@ff.ulisboa.pt.
authors.forename: Rita C
authors.initials: RC
authors.lastname: Guedes
authors.affiliation: Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal. ngoliveira@ff.ulisboa.pt.
authors.forename: Nuno G
authors.initials: NG
authors.lastname: Oliveira
mesh_terms: D045744:Cell Line, Tumor; D004260:DNA Repair; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase / Q000037:antagonists & inhibitors*; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D020128:Inhibitory Concentration 50; D008024:Ligands; D062105:Molecular Docking Simulation; D011994:Recombinant Proteins / Q000187:drug effects; D013050:Spectrometry, Fluorescence
chemical_list: D004791:Enzyme Inhibitors; D008024:Ligands; D011994:Recombinant Proteins; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase
keywords: APE1 inhibitors; BER pathway; DNA damage; cancer; drug discovery; molecular docking; virtual screening