Molecular Modeling Study Of Protooncogene PIM-1Kinase Inhibitors

Targeted inhibition of protein kinases has become an attractive therapeutic strategy in the treatment of cancer. Molecular simulation techniques have been widely applied to design and discovery of small molecule protein kinase inhibitors. Protooncogene PIM (Provirus Integration site for Moloney murine leukemia virus) kinases have been shown to have diverse biological roles in cell survival, proliferation, differentiation and apoptosis, as well as play an important role in tumor occurrence and development. Overexpression of the PIM-1kinase has been found that can promote cell cycle progression and inhibit apoptosis of cells. It has been confirmed that inhibition of cancer cells growth by inhibition of the PIM-1kinase, so the PIM-1kinase has been widely considered as attractive target for the development of anticancer drugs.In this thesis, in order to provide theoretical foundation and reference for designing novel and potent inhibitors of the PIM-1kinase and virtual screening for lead discovery, the inhibition mechanism of some PIM-1kinase inhibitors were studied as well as inhibitor activity were calculated and predicted by molecular modeling, including molecular docking, molecular dynamics and binding free energy calculations, and three-dimensional quantitative structure-activity relationship (3D QSAR). The thesis included seven chapters and presented as follows:Chapter1The research background, methodology and content of this thesis were introduced.Chapter2The research progress of PIM-1kinase inhibitors in experimental and theoretical calculation was summarized.Chapter3The effect of the residues flexibility of PIM-1kinase on the inhibitor binding mode prediction was studied. Firstly, through self-docking of15PIM-1kinase inhibitor complexs, Goldscore has been confirmed that is the most suitable scoring function for prediction of inhibitor binding mode. Then cross docking and comparative analysis of crystal structure determined that the prediction of binding mode of inhibitors are affected by G-loop flexibility as well as the orientation of the side chains of Lys67and Glu89.Chapter4The binding mode of lead inhibitors SMI-4a was predicted and identified. Firstly, two different binding modes of SMI-4a were obtained by molecular docking, and then the two different complex structures of SMI-4a/PIM-1kinase were calculated by molecular dynamics simulation. Subsequently, the correspondingly binding free energies were estimated with the Molecular Mechanics-Poisson Boltzmann surface area (MM-PBSA) approach. Moreover, through analyzing the computed MM/PBSA results, the preferential binding mode was determined.Chapter5The inhibition mechanism of isoxazole quinoline-diones as PIM-1kinase inhibitors was studied, and new compounds were designed. Firstly, the binding modes of inhibitors were obtained by molecular docking, and the correlation between scoring and binding affinity was analyzed. Then molecular dynamics simulations of the inhibitors/PIM-1kinase complexes were conducted. Subsequently, the interaction energies of inhibitors and PIM-1kinase were calculated by linear interaction energy (LIE) approach. The LIE model was established, and the prediction accuracy of the binding affinity was analyzed. Finally, based on the binding mode and the inhibition activity of the inhibitors, the feasible optimization position of isoxazole quinoline-diones compounds was proposed, and three new compounds were designed to confirm the feasible optimization position.Chapter6The feasibility and accuracy of linear response-MMPBSA (LR-MM-PBSA) approach to predict the binding affinity of benzothiophene pyrimidinones as PIM-1kinase inhibitors were analyzed. Firstly, the binding modes of the inhibitors were obtained by molecular docking, and the correlation between scoring and binding affinity was analyzed. Then the structures of the complexs were optimized, and the binding free energies were calculated by MM-PBSA. All the compounds were divided into training and test set, the LR-MM-PBSA model was established using the training set, and it was used to predict the binding affinity of the remaining compounds.Chapter7The inhibition mechanism of triazolopyridines as PIM-1kinase inhibitors was analyzed by molecular docking and3D QSAR metheds. Firstly, the active conformations of the inhibitors were obtained by the molecular docking. Then CoMFA model and CoMSIA model were builded based on the docked conformations. Both the CoMFA model and CoMSIA model can successfully predict the compound activity. The inhibitive mechanism of triazolepyridines compounds was analyzed by the overlap of the active site and the three-dimensional equipotential surface map of CoMFA model and CoMSIA model.