Computational Study of Binding Energy of Protein-Ligand Complexes for Two Kinases: Thermodynamic Integration Molecular Dynamics and Docking Simulation

• Main Author: 吳冠緯
• Other Authors: 孫英傑
• Format: Others
• Language: zh-TW
• Published: 2011
• Online Access: http://ndltd.ncl.edu.tw/handle/86923683324881538499

碩士 === 國立臺灣師範大學 === 化學系 === 100 === Cancer has been one of the top ten leading causes of death for several decades. The target drugs research for cancer therapy is now a popular field among international medicinal chemists. Because of the significant amount of money and human resources spent in the drug development process, computer-aided drug design method is an attractive tool to reduce cost and assist drug discovery. Protein kinases are one of the protein families which are drug targets for cancer therapy. Here, we selected two kinases, which are ERK2 and FGFR1 kinases, and used computer modeling to investigate binding energy of inhibitor-protein complexes for these two kinases. In the part of ERK2, we used thermodynamic integration MD method to compute relative binding free energy of several ERK2-inhibitor complexes of interest. We carried out computations to predict G for new analogs, focusing on placing polar and nonpolar functional groups at the meta site of benzene ring, to see if these ligands have better binding affinity than the above ligands. The computations resulted that a ligand with polar –OH group has better binding affinity than the previous examined ligand by ~2.0 kcal/mol and two other ligands have better affinity by ~1.0 kcal/mol. The predicted better inhibitors of this kind should be of interest to experimentalists for future experimental enzyme and/or cell assays. In addition to TI-MD simulation, we also worked on interactions of FGFR1 kinase-inhibitor complexes using docking computation, focusing on how enrichment factor (EF) enhances in virtual screening by including side chain movement and applying hydrogen bond constraint for this kinase. To this end, active and decoy compounds from the Directory of Useful Decoys 1 database was obtained and benchmarked with GOLD program. Interestingly, among combinations of side chains which were allowed to move, EF is significantly higher with movement of Lys514 compared with others. In addition, the effect of adding hydrogen bond constraint at a residue located in the hinge segment, Ala564, was also examined. The results were analyzed and discussed. The present results should be useful for virtual screening of large databases against this kinase.