Structure‐Based Pharmacophore Modeling from Multicomplex: a Comprehensive Pharmacophore Generation of Protein Kinase CK2 and Virtual Screening Based on it for Novel Inhibitors

Abstract

Protein kinase CK2, a member of the serine/threonine kinase family, is an attractive therapeutic target for anticancer combination therapy. A multiple structure-based modeling approach complemented with shape components was taken to build a reliable pharmacophore model for ATP-competitive CK2 inhibitors. The final model consisted of one hydrogen bond acceptor (HBA), one hydrogen bond donor (HBD), two hydrophobic (HY) features, several excluded volumes and shape constraints. In the validation study, this model yielded an enrichment factor of 10.22 and performed fairly well in distinguishing active compounds. SPECS database was searched based on this query and sixteen compounds were retained after multiple filtrations for biological test. 4 compounds with IC50 values less than 10 µM were disclosed, providing 2 new chemical scaffolds as CK2 inhibitors. It is expected that the information provided here is helpful for discovering more potential CK2 inhibitors.

LYG-202 Augments Tumor Necrosis Factor-α-Induced Apoptosis via Attenuating Casein Kinase 2-Dependent Nuclear Factor-κB Pathway in HepG2 Cells

“…In addition, CK2 has been found to show increased protein expression levels and nuclear localization in cancer cells compared with those in their normal counterparts. These findings promote CK2 as an unfavorable prognostic marker in several cancers and consequently as a relevant therapeutic target (Prudent et al, 2010;Sun et al, 2010;Trembley et al, 2010). Recent studies report that CK2 contributes to aberrant NF-B activation though enhancement of IKK␤ activity for the phosphorylation of the Ser32/Ser36 NH 2 terminus of IB␣, a novel and distinct function from that of CK2 as a known COOH-terminal IKK␤ (Yu et al, 2006;Brown et al, 2010).…”

“…The effect of LYG-202 on IKK␤ activity was determined using the HTScan IKK␤ kinase assay kit (Cell Signaling Technology) as described previously (Sun et al, 2010).…”

“…We used our protein-ligand docking software package GOLD to dock LYG-202 into many potential drug targets that could activate IKK␤ activity (Hayden and Ghosh, 2004;Schmid and Birbach, 2008). Molecular docking was performed following the method of Sun et al (2010). We then ranked each protein according to the GOLD fitness score.…”

“…at ASPET Journals on May 10, 2018 molpharm.aspetjournals.org ular docking analysis showed that LYG-202 had hydrogen bonds with Asp175 and Asn118, which were essential for CK2 activity (Sun et al, 2010), in the binding pocket of CK2; moreover, it inhibited TNF-␣-induced CK2 activity but had no effect on its expression (Fig. 5, B and C).…”

“…at ASPET Journals on May 10, 2018 molpharm.aspetjournals.org assay kit (MBL International, Woburn, MA) according to the manufacturer's instruction (Sun et al, 2010). Down-Regulation of CK2 by siRNA.…”