The Design And Research Of Anticancer Drugs Based On CDK2

Cyclin dependent kinase (CDK) is a family of Serine/Threonine proteinkinase, which controls the cell cycle. The disorder of CDK/cyclin would causethe abnormal expression of cell cycle, and it is the key reason of cancer. In thisfamily, CDK2is a very important member and we can try to treat cancer by usingthe opportunity of inhibiting its activity.In this thesis, we studied the interaction between CDK2and two seriescompounds (pyramiding and pyramiding derivatives and2,6,9-trisubstitutedpurine derivatives) and designed two novel inhibitors of CDK2based on that byusing molecular docking and molecular dynamics simulation. The results showthat both of these two series compounds form stable hydrogen bonds with someimportant residues in the active site of CDK2. Moreover, the docking energiesand binding free energies between these compounds and CDK2are in consistentwith IC50value of experiment assays. In addition, Van de Waals energy, Coulombenergy, polar solvent energy and nonpolar solvent energy constitute binding freeenergy.And Van de Waals energy, Coulomb energy and nonpolar solvent energyplay key role in the binding free energy because they are negative. In anotherhand, we found that the amino acid ILE10, VAL18, GLN85and LEU134are thepredominant amino acid in the binding site of CDK2among the enzyme-inhibitorcomplex mentioned previously. So we can think that it would be helpful thatadding more hydrophobic groups in the inhibitor molecule. We also found thatthe inhibitor would be better when the compounds with larger bulk. Based on theknowledge, we designed two new compounds and studied its interaction withCDK2. The result shows that this new molecule has better inhibition to CDK2than the compounds used previously. This paper would provide theoretical support to the novel inhibitor designation for anti-tumor on CDK2target.