title: Pharmacophore-Based Virtual Screening to Discover New Active Compounds for Human Choline Kinase α1.
abstract: Choline kinase (CK) catalyses the transfer of the ATP γ-phosphate to choline to generate phosphocholine and ADP in the presence of magnesium leading to the synthesis of phosphatidylcholine. Of the three isoforms of CK described in humans, only the α isoforms (HsCKα) are strongly associated with cancer and have been validated as drug targets to treat this disease. Over the years, a large number of Hemicholinium-3 (HC-3)-based HsCKα biscationic inhibitors have been developed though the relevant common features important for the biological function have not been defined. Here, selecting a large number of previous HC-3-based inhibitors, we discover through computational studies a pharmacophore model formed by five moieties that are included in the 1-benzyl-4-(N-methylaniline)pyridinium fragment. Using a pharmacophore-guided virtual screening, we then identified 6 molecules that showed binding affinities in the low μM range to HsCKα1. Finally, protein crystallization studies suggested that one of these molecules is bound to the choline and ATP-binding sites. In conclusion, we have developed a pharmacophore model that not only allowed us to dissect the structural important features of the previous HC-3 derivatives, but also enabled the identification of novel chemical tools with good ligand efficiencies to investigate the biological functions of HsCKα1.
authors.affiliation: Department of Pharmaceutical and Organic Chemistry, Faculty of Pharmacy, University of Granada, Campus Cartuja, Granada 18071, Spain phone: +34 958 243848.
authors.forename: Lucía
authors.initials: L
authors.lastname: Serrán-Aguilera
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Università degli Studi di Perugia, Via del Liceo, 1, 06123 Perugia, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Nuti
authors.affiliation: Department of Pharmaceutical and Organic Chemistry, Faculty of Pharmacy, University of Granada, Campus Cartuja, Granada 18071, Spain phone: +34 958 243848.
authors.forename: Luisa C
authors.initials: LC
authors.lastname: López-Cara
authors.affiliation: Department of Pharmaceutical and Organic Chemistry, Faculty of Pharmacy, University of Granada, Campus Cartuja, Granada 18071, Spain phone: +34 958 243848.
authors.forename: Miguel Á Gallo
authors.initials: MÁ
authors.lastname: Mezo
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Università degli Studi di Perugia, Via del Liceo, 1, 06123 Perugia, Italy. antonio@chimfarm.unipg.it.
authors.forename: Antonio
authors.initials: A
authors.lastname: Macchiarulo
authors.affiliation: Department of Pharmaceutical and Organic Chemistry, Faculty of Pharmacy, University of Granada, Campus Cartuja, Granada 18071, Spain phone: +34 958 243848. aentrena@ugr.es.
authors.forename: Antonio
authors.initials: A
authors.lastname: Entrena
authors.affiliation: Institute of Biocomputation and Physics of Complex Systems (BIFI) and BIFI-IQFR (CSIC) Joint Unit, University of Zaragoza, Campus Río Ebro, Zaragoza 50018, Spain; Edificio I+D; Fundación ARAID, Edificio Pignatelli 36, Spain phones: +39 075 5855160; +34 976 762997. rhurtado@bifi.es.
authors.forename: Ramón
authors.initials: R
authors.lastname: Hurtado-Guerrero
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry*; D002797:Choline Kinase / Q000037:antagonists & inhibitors / Q000737:chemistry; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000737:chemistry*; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000737:chemistry; D008958:Models, Molecular; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry; D009369:Neoplasms / Q000188:drug therapy / Q000201:enzymology*
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D009363:Neoplasm Proteins; C517212:CHKA protein, human; D002797:Choline Kinase
keywords: Binding; Choline kinase; Crystallization; Hits; Pharmacophore model; Tryptophan fluorescence; Virtual screening