Molecular Simulation Studies Of Structure And Activity Of Two Cancer-Related Enzymes

This experiment eventually determined the binding modes and the factors affecting binding free energy of glucose-6-phosphate dehydrogenase(G6PD) with derivatives inhibitors and glucose-6-phosphate dehydrogenase(6PGDH) with its natural substrate catalytic intermediates, through protein and small molecule inhibitors structure preparation, molecular docking, Amber molecular dynamics simulation, and the MM-PBSA method of binding free energy calculation. With getting molecular docking modes and factors affecting binding free energy of two systems, ultimately, we could make guidance of the design and synthesis of more potential inhibitors of G6 PD and6PGDH, and know important significances of antitumor drug research and development by inhibiting the activitives of G6 PD and 6PGDH.Molecular docking reveals that the binding mode of G6PD-inhibitors and the results of binding free energy calculation shows that hydrophobic interaction plays a very important role on binding modes of G6 PD and derivatives inhibitors. Further analysis shows that the presence of non polar bonds and its biggest contribution on binding free energy, especially for Van der Waals’ force. At the same time,G6PD-inhibitors owes four strong hydrogen bonds, which play an important role on the localization of the inhibitor and binding free energy. Similarly, this experimental results shows that the structure and properties of two kinds of 6PGDH enzymes are very similar, whose conformations of combination site are basically similar, with different arrangements on the amino acid sequence. The cause of the different inhibitting effects of the same inhibitors may be due to the conformational differences of binding sites.Molecular docking and molecular dynamics simulation shows that seven amino acids residues of 6PGDH and 6-phospho Gluconate and its derivatives could form several hydrogen bonds, such as Lys262, Tyr193 and Arg289 of T.brucei 6PGDH and Lys260,Tyr191 and Arg287 of Sheep 6PGDH, which plays an important role on the localization of the inhibitors and the contribution of binding free energy, by the results of the Molecular Mechanics-Poisson-Boltzmann Surface Area(MM-PBSA) method of binding free energy calculation. In a word, the design of G6 PD inhibitors can introduce more benzene, carbon chain and hydrophobic functional groups and 6PGDH inhibitor design can introduce the polar functional groups, such as hydroxyl, amino and carboxyl.