000057730 001__ 57730
000057730 005__ 20210121114533.0
000057730 0247_ $$2doi$$a10.1002/minf.201400140
000057730 0248_ $$2sideral$$a90931
000057730 037__ $$aART-2015-90931
000057730 041__ $$aeng
000057730 100__ $$aSerrán-Aguilera, L.
000057730 245__ $$aPharmacophore-Based Virtual Screening to Discover New Active Compounds for Human Choline Kinase a1
000057730 260__ $$c2015
000057730 5060_ $$aAccess copy available to the general public$$fUnrestricted
000057730 5203_ $$aCholine kinase (CK) catalyses the transfer of the ATP gamma-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 a isoforms (HsCK alpha) 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 HsCK alpha 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 mM range to HsCK alpha 1. 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 HsCK alpha 1.
000057730 536__ $$9info:eu-repo/grantAgreement/ES/MICINN/SAF2009-11955$$9info:eu-repo/grantAgreement/ES/MICINN/BFU2010-19504$$9info:eu-repo/grantAgreement/ES/MICINN/AP2009-0555$$9info:eu-repo/grantAgreement/EC/FP7/283570/EU/Transnational access and enhancement of integrated Biological Structure determination at synchrotron X-ray radiation facilities/BIOSTRUCT-X
000057730 540__ $$9info:eu-repo/semantics/openAccess$$aAll rights reserved$$uhttp://www.europeana.eu/rights/rr-f/
000057730 590__ $$a1.57$$b2015
000057730 591__ $$aCOMPUTER SCIENCE, INTERDISCIPLINARY APPLICATIONS$$b49 / 104 = 0.471$$c2015$$dQ2$$eT2
000057730 591__ $$aMATHEMATICAL & COMPUTATIONAL BIOLOGY$$b23 / 56 = 0.411$$c2015$$dQ2$$eT2
000057730 591__ $$aCHEMISTRY, MEDICINAL$$b41 / 59 = 0.695$$c2015$$dQ3$$eT3
000057730 592__ $$a0.592$$b2015
000057730 593__ $$aOrganic Chemistry$$c2015$$dQ2
000057730 593__ $$aDrug Discovery$$c2015$$dQ2
000057730 593__ $$aComputer Science Applications$$c2015$$dQ2
000057730 593__ $$aStructural Biology$$c2015$$dQ3
000057730 593__ $$aMolecular Medicine$$c2015$$dQ3
000057730 655_4 $$ainfo:eu-repo/semantics/article$$vinfo:eu-repo/semantics/submittedVersion
000057730 700__ $$aNuti, R.
000057730 700__ $$aLõpez-Cara, L.C.
000057730 700__ $$aMezo, M.Á.G.
000057730 700__ $$aMacchiarulo, A.
000057730 700__ $$aEntrena, A.
000057730 700__ $$0(orcid)0000-0002-3122-9401$$aHurtado-Guerrero, R.
000057730 773__ $$g34, 6-7 (2015), 458-466$$pMOLECULAR INFORMATICS$$tMOLECULAR INFORMATICS$$x1868-1743
000057730 8564_ $$s1910789$$uhttps://zaguan.unizar.es/record/57730/files/texto_completo.pdf$$yPreprint
000057730 8564_ $$s123462$$uhttps://zaguan.unizar.es/record/57730/files/texto_completo.jpg?subformat=icon$$xicon$$yPreprint
000057730 909CO $$ooai:zaguan.unizar.es:57730$$particulos$$pdriver
000057730 951__ $$a2021-01-21-11:11:42
000057730 980__ $$aARTICLE