title: Comparing Drug Images and Repurposing Drugs with BioGPS and FLAPdock: The Thymidylate Synthase Case.
abstract: Repurposing and repositioning drugs has become a frequently pursued and successful strategy in the current era, as new chemical entities are increasingly difficult to find and get approved. Herein we report an integrated BioGPS/FLAPdock pipeline for rapid and effective off-target identification and drug repurposing. Our method is based on the structural and chemical properties of protein binding sites, that is, the ligand image, encoded in the GRID molecular interaction fields (MIFs). Protein similarity is disclosed through the BioGPS algorithm by measuring the pockets' overlap according to which pockets are clustered. Co-crystallized and known ligands can be cross-docked among similar targets, selected for subsequent in vitro binding experiments, and possibly improved for inhibitory potency. We used human thymidylate synthase (TS) as a test case and searched the entire RCSB Protein Data Bank (PDB) for similar target pockets. We chose casein kinase IIα as a control and tested a series of its inhibitors against the TS template. Ellagic acid and apigenin were identified as TS inhibitors, and various flavonoids were selected and synthesized in a second-round selection. The compounds were demonstrated to be active in the low-micromolar range.
authors.affiliation: Molecular Discovery Limited, 215 Marsh Road, Pinner Middlesex, London, HA5 5NE, UK.
authors.forename: Lydia
authors.identifier: 0000-0003-4596-7242
authors.initials: L
authors.lastname: Siragusa
authors.affiliation: Department of Life Sciences, University of Modena and Reggio Emilia, Via Campi 103, 41125, Modena, Italy.
authors.forename: Rosaria
authors.initials: R
authors.lastname: Luciani
authors.affiliation: Department of Life Sciences, University of Modena and Reggio Emilia, Via Campi 103, 41125, Modena, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Borsari
authors.affiliation: Department of Life Sciences, University of Modena and Reggio Emilia, Via Campi 103, 41125, Modena, Italy.
authors.forename: Stefania
authors.identifier: 0000-0003-1149-5953
authors.initials: S
authors.lastname: Ferrari
authors.affiliation: Department of Life Sciences, University of Modena and Reggio Emilia, Via Campi 103, 41125, Modena, Italy.
authors.forename: Maria Paola
authors.identifier: 0000-0002-0443-5402
authors.initials: MP
authors.lastname: Costi
authors.affiliation: Department of Chemistry, Biology and Biotechnology, University of Perugia, Via Elce di Sotto 8, 06123, Perugia, Italy.
authors.forename: Gabriele
authors.identifier: 0000-0002-4162-8692
authors.initials: G
authors.lastname: Cruciani
authors.affiliation: Department of Life Sciences, University of Modena and Reggio Emilia, Via Campi 103, 41125, Modena, Italy. francesca.spyrakis@unipr.it.|Department of Food Science, University of Parma, Viale delle Scienze 17A, 43124, Parma, Italy. francesca.spyrakis@unipr.it.
authors.forename: Francesca
authors.identifier: 0000-0002-4016-227X
authors.initials: F
authors.lastname: Spyrakis
mesh_terms: D000465:Algorithms; D047310:Apigenin / Q000737:chemistry; D001665:Binding Sites; D047390:Casein Kinase II / Q000737:chemistry; D003856:Deoxyuracil Nucleotides / Q000737:chemistry; D058492:Drug Repositioning / Q000379:methods*; D004610:Ellagic Acid / Q000737:chemistry; D006801:Humans; D006860:Hydrogen Bonding; D008024:Ligands; D062105:Molecular Docking Simulation / Q000379:methods*; D047428:Protein Kinase Inhibitors / Q000737:chemistry; D017434:Protein Structure, Tertiary; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D014867:Water / Q000737:chemistry
chemical_list: D003856:Deoxyuracil Nucleotides; D008024:Ligands; D047428:Protein Kinase Inhibitors; D014867:Water; D004610:Ellagic Acid; D047310:Apigenin; C007267:2'-deoxyuridylic acid; D013940:Thymidylate Synthase; D047390:Casein Kinase II
keywords: cross docking; drug discovery; drug repurposing; thymidylate synthase; virtual screening