title: Coumarin as attractive casein kinase 2 (CK2) inhibitor scaffold: an integrate approach to elucidate the putative binding motif and explain structure-activity relationships.
abstract: Casein kinase 2 (CK2) is an ubiquitous, essential, and highly pleiotropic protein kinase whose abnormally high constitutive activity is suspected to underlie its pathogenic potential in neoplasia and other diseases. Recently, using different virtual screening approaches, we have identified several novel CK2 inhibitors. In particular, we have discovered that coumarin moiety can be considered an attractive CK2 inhibitor scaffold. In the present work, we have synthetized and tested a small library of coumarins (more than 60), rationalizing the observed structure-activity relationship. Moreover, the most promising inhibitor, 3,8-dibromo-7-hydroxy-4-methylchromen-2-one (DBC), has been also crystallized in complex with CK2, and the experimental binding mode has been used to derive a linear interaction energy (LIE) model.
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Università di Padova, via Marzolo 5, Padova, Italy.
authors.forename: Adriana
authors.initials: A
authors.lastname: Chilin
authors.forename: Roberto
authors.initials: R
authors.lastname: Battistutta
authors.forename: Andrea
authors.initials: A
authors.lastname: Bortolato
authors.forename: Giorgio
authors.initials: G
authors.lastname: Cozza
authors.forename: Samuele
authors.initials: S
authors.lastname: Zanatta
authors.forename: Giorgia
authors.initials: G
authors.lastname: Poletto
authors.forename: Marco
authors.initials: M
authors.lastname: Mazzorana
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Zagotto
authors.forename: Eugenio
authors.initials: E
authors.lastname: Uriarte
authors.forename: Adriano
authors.initials: A
authors.lastname: Guiotto
authors.forename: Lorenzo A
authors.initials: LA
authors.lastname: Pinna
authors.forename: Flavio
authors.initials: F
authors.lastname: Meggio
authors.forename: Stefano
authors.initials: S
authors.lastname: Moro
mesh_terms: D020816:Amino Acid Motifs; D001665:Binding Sites; D047390:Casein Kinase II / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D002867:Chromones / Q000138:chemical synthesis* / Q000737:chemistry; D003374:Coumarins / Q000138:chemical synthesis* / Q000737:chemistry; D018360:Crystallography, X-Ray; D011485:Protein Binding; D013329:Structure-Activity Relationship; D013816:Thermodynamics; D003313:Zea mays
chemical_list: C528849:3,8-dibromo-7-hydroxy-4-methylchromen-2-one; D002867:Chromones; D003374:Coumarins; D047390:Casein Kinase II