Pharmacophore-Based Virtual Screening to Discover New Active Compounds for Human Choline Kinase a1

Serrán-Aguilera, L. ; Nuti, R. ; Lõpez-Cara, L.C. ; Mezo, M.Á.G. ; Macchiarulo, A. ; Entrena, A. ; Hurtado-Guerrero, R.

Resumen: 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.

Idioma: Inglés

DOI: 10.1002/minf.201400140

Año: 2015

Publicado en: MOLECULAR INFORMATICS 34, 6-7 (2015), 458-466
ISSN: 1868-1743

Factor impacto JCR: 1.57 (2015)

Categ. JCR: COMPUTER SCIENCE, INTERDISCIPLINARY APPLICATIONS rank: 49 / 104 = 0.471 (2015) - Q2 - T2
Categ. JCR: MATHEMATICAL & COMPUTATIONAL BIOLOGY rank: 23 / 56 = 0.411 (2015) - Q2 - T2
Categ. JCR: CHEMISTRY, MEDICINAL rank: 41 / 59 = 0.695 (2015) - Q3 - T3

Factor impacto SCIMAGO: 0.592 - Organic Chemistry (Q2) - Drug Discovery (Q2) - Computer Science Applications (Q2) - Structural Biology (Q3) - Molecular Medicine (Q3)

Financiación: 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
Financiación: info:eu-repo/grantAgreement/ES/MICINN/AP2009-0555
Financiación: info:eu-repo/grantAgreement/ES/MICINN/BFU2010-19504
Financiación: info:eu-repo/grantAgreement/ES/MICINN/SAF2009-11955

Tipo y forma: Article (PrePrint)