Coumarin as attractive casein kinase 2 (CK2) inhibitor scaffold: an integrate approach to elucidate the putative binding motif and explain structure-activity relationships.
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.
Chilin
Adriana
A
Dipartimento di Scienze Farmaceutiche, Università di Padova, via Marzolo 5, Padova, Italy.
Battistutta
Roberto
R
Bortolato
Andrea
A
Cozza
Giorgio
G
Zanatta
Samuele
S
Poletto
Giorgia
G
Mazzorana
Marco
M
Zagotto
Giuseppe
G
Uriarte
Eugenio
E
Guiotto
Adriano
A
Pinna
Lorenzo A
LA
Meggio
Flavio
F
Moro
Stefano
S
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
C528849:3,8-dibromo-7-hydroxy-4-methylchromen-2-one; D002867:Chromones; D003374:Coumarins; D047390:Casein Kinase II