| Summary: | 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.
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