Identification of novel protein kinase CK1 delta (CK1delta) inhibitors through structure-based virtual screening.
In eukaryotes, protein phosphorylation of serine, threonine or tyrosine residues by protein kinases plays an important role in many cellular processes. Members of the protein kinase CK1 family usually phosphorylate residues of serine that are close to other phosphoserine in a consensus motif of pS-X-X-S, and they are implicated in the regulation of a variety of physiological processes as well as in pathologies like cancer and Alzheimer's disease. Using a structure-based virtual screening (SBVS) approach we have identified two anthraquinones as novel CK1delta inhibitors. These amino-anthraquinone analogs (derivatives 1 and 2) are among the most potent and selective CK1delta inhibitors known today (IC(50)=0.3 and 0.6 microM, respectively).
Cozza
Giorgio
G
Molecular Modeling Section, Dipartimento di Scienze Farmaceutiche, Università di Padova, via Marzolo 5, 35131 Padova, Italy.
Gianoncelli
Alessandra
A
Montopoli
Monica
M
Caparrotta
Laura
L
Venerando
Andrea
A
Meggio
Flavio
F
Pinna
Lorenzo A
LA
Zagotto
Giuseppe
G
Moro
Stefano
S
D000880:Anthraquinones / Q000737:chemistry; D047389:Casein Kinase I / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D002626:Chemistry, Pharmaceutical / Q000379:methods; D003198:Computer Simulation; D015195:Drug Design; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D006801:Humans; D020128:Inhibitory Concentration 50; D008968:Molecular Conformation; D010766:Phosphorylation; D020033:Protein Isoforms; D012984:Software; D014443:Tyrosine / Q000737:chemistry
D000880:Anthraquinones; D004791:Enzyme Inhibitors; D020033:Protein Isoforms; D014443:Tyrosine; D047389:Casein Kinase I