57730 20210121114533.0 doi 10.1002/minf.201400140 sideral 90931 ART-2015-90931 eng Serrán-Aguilera, L. Pharmacophore-Based Virtual Screening to Discover New Active Compounds for Human Choline Kinase a1 2015 Access copy available to the general public Unrestricted Choline 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. info:eu-repo/grantAgreement/ES/MICINN/SAF2009-11955 info:eu-repo/grantAgreement/ES/MICINN/BFU2010-19504 info:eu-repo/grantAgreement/ES/MICINN/AP2009-0555 info:eu-repo/grantAgreement/EC/FP7/283570/EU/Transnational access and enhancement of integrated Biological Structure determination at synchrotron X-ray radiation facilities/BIOSTRUCT-X info:eu-repo/semantics/openAccess All rights reserved http://www.europeana.eu/rights/rr-f/ 1.57 2015 COMPUTER SCIENCE, INTERDISCIPLINARY APPLICATIONS 49 / 104 = 0.471 2015 Q2 T2 MATHEMATICAL & COMPUTATIONAL BIOLOGY 23 / 56 = 0.411 2015 Q2 T2 CHEMISTRY, MEDICINAL 41 / 59 = 0.695 2015 Q3 T3 0.592 2015 Organic Chemistry 2015 Q2 Drug Discovery 2015 Q2 Computer Science Applications 2015 Q2 Structural Biology 2015 Q3 Molecular Medicine 2015 Q3 info:eu-repo/semantics/article info:eu-repo/semantics/submittedVersion Nuti, R. Lõpez-Cara, L.C. Mezo, M.Á.G. Macchiarulo, A. Entrena, A. (orcid)0000-0002-3122-9401 Hurtado-Guerrero, R. 34, 6-7 (2015), 458-466 MOLECULAR INFORMATICS MOLECULAR INFORMATICS 1868-1743 1910789 http://zaguan.unizar.es/record/57730/files/texto_completo.pdf Preprint 123462 http://zaguan.unizar.es/record/57730/files/texto_completo.jpg?subformat=icon icon Preprint oai:zaguan.unizar.es:57730 articulos driver 2021-01-21-11:11:42 ARTICLE