Design And Screening Of Small Molecular Inhibitors For Protein Kinase CK2and PAK4

Protein kinases CK2and PAK4are highly conserved serine/threonine proteinkinases, which are related to various cellular events and are overexpressed in numeroustumors. Therefore, they are importanttherapeutic targets for related cancers and thedesign of the inhibitors against CK2and PAK2are quite important.Firstly, we attempted to gain more insight into the inhibition process of CK2by aseries of CX-4945derivatives through an integrated computational study that combinesmolecular docking, molecular dynamics (MD) simulations, and binding free energycalculations in this paper. Based on the binding poses predicted by molecular docking,the MD simulations were performed to explore the dynamic binding processes for tenselected inhibitors. Then, both Molecular Mechanics/Poisson Boltzmann Surface Area(MM/PBSA) and Molecular Mechanics/Generalized Born Surface Area (MM/GBSA)techniques were employed to predict the binding free energies of the studied inhibitors.The predicted binding free energies of the selected inhibitors correlate well with theirexperimental activities (r2=0.78), and the van der Waals term is the most favorablecomponent for the total energies. The free energy decomposition on a per residue basisreveals that the residue K68is essential for the electrostatic interactions between CK2and the studied inhibitors and a numerous residues, including L45, V53, V66, F113,M163, and I174, play critical roles in forming van der Waals interactions with theinhibitors. Finally, a number of new compounds were designed and the binding affinityand the predicted binding free energies of each designed molecule were obtained onthe basis of molecular docking and MM/PBSA. It is expected that our research willbenefit to the future rational design of novel and potent inhibitors of CK2.In the second part of this thesis, in order to find potent inhibitors of PAK4, Glide docking was employed to identify potential molecules that can interact with PAK4from two chemical databases, including ChemBridge and Specs, with~1.1millioncompounds. Based on the filtering of the REOS rules and structural clustering,148compounds were chosen and purchased, which were submitted to the biologicalexperiments. The in vitro kinase-based assay illustrates that seven compounds havebetter inhibitory activities against PAK4than the others. Further, two of them showobvious activities at the cellular level, with their IC50values about15μM in thesubsequent cell viability assay. These two compounds are potential lead compounds fortreating PAK4-related cancers.