Study On The Virtual Screening And Anti-cancer Activity Of Novel Protein Kinase CK2 Inhibitors

Cancer is one of the threats to human health and life,and it is the challenging and significant work to discovery anti-cancer drugs.Protein kinase CK2(CK2)is involved in a variety of physiological event such as cell growth,division and apoptosis,and thus is closely related to the occurrence and development of cancer.Consequently,this attractive kinase has been considered as an appealing target for the development of inhibitors with pharmacological potential.Due to the disadvantages of CK2α ATP-compective inhibitors,such as poor selectivity,toxic effects and low drug-like,no drug has entered into the clinical use.Except CX-4945(in a phase II clinical trial)based on high-throughput screening method obtained,the efficient and successful screening strategy is crucialfor potential and drug-like CK2α inhibitors.Here we described an application of virtual screening research to discover novel and potent CK2α leads from the natural product database.1.Three-dimensional quantitative structure-activity relationship study of natural product flavonesThe nature product flavones analogues inhibit CK2α with high biological activities,which are closely related to the property and position of substituents.In the present work,a series of flavones analogues were studied by utilizing a combination of three-dimensional quantitative structure activity relationship,molecular docking,and molecular dynamics simulation methods.The CoMFA and CoMSIA analyses were done using ligand-based(LB)and receptor-based(RB)alignment schemes,and the RB CoMSIA model showed good correlative and predictive ability.By combing the contour maps of RB CoMSIA model with the binding pocket of CK2α,the optimization clues for inhibitory activity improvement were proposed.And the molecular dynamics simulation results indicted the hydrogen bond between pharmacophore groups and hinge reagion is essential for the compounds with high inhibitory activity against CK2α.2.Pharmacophore model construction of CK2α inhibitors and recognize its key pharmacophore groupsConsidering the variety of molecular scaffolds and coverage of inhibitory activity values,a total of 48 inhibitors were selected to build the pharmacophore model using HypoGen algorithm of Discovery Studio 3.1.The best model Hypo 1 consisted of four features,one hydrogen bond acceptor(HBA),one hydrogen donor(HBD),one hydrophobic feature(HY)and one ring aromatic feature(RA).And also the comparative mapping analysis between the four pharmacophore features and the higher,moderate and the lower active inhibitors were elucidated.These results provided the value information for the design and virtual screening of anti-cancer CK2α inhibitors.3.Virtual screening and biological activity of CK2α inhibitorsNatural products are one of the most important resources of anti-cancer lead compounds.The well validated Hypo 1 was used as a 3D query to screen the natural product database,and then retaining moleculeswere subjected to filter based on the binding modes,predicted inhibitory activity,Lipinski’s rule-of-five and ADMET properties to obtain the theoretical hits molecules.And then inhibitory activities against CK2α and cancer cell proliferation of selected compounds were evaluated.Chalcone(6)and Bergaptol(10)presented the potential against CK2α and lung(A549)and(HepG2)cancer cell lines.Comparative analysis of binding mode of compound CX-4945 、 E9 and chalcone with CK2α active pocket provideed the hints of fragment-based chalcone deviates design.To sum up,the pharmacophore model,3D-QSAR,docking and other technologies were employed for virtual screening study to natural products.And the virtual screening result and lead compound optimization study will be helpful for the development of CK2α inhibitors and potent anti-cancer drugs.