Theoretical Studies On Structure Prediction For Catalytic Domain Of MMP26 And Molecular Docking With MMP Inhibitors

With the rapid development of computer technology, computer aided molecular modeling has become a very important and active research field in chemistry, biochemistry and molecular biology. In this thesis, molecular dynamics simulations, quantum chemical calculation methods are used to build three dimensional models for MMP26 and study its structure propertie and the binding mode with drag in detail. Some creative results were obtained from the methods mentioned above.Matrix Metalloproteinases (MMPs) are a family of zinc metallo-endopeptidases secreted by cells, and are responsible for much of the turnover of matrix components. The MMPs are involved in a wide range of proteolytic events, in normal and pathological circumstances; pathological processes involving MMPs include tumor growth and migration, fibrosis, arthritis, glaucoma, lupus scleroderma, cirrhosis, multiple sclerosis, aortic aneurysms, infertility, and many more diseases. The MMPs are over-expressed during invasion and metastasis and degrade extracellular matrix, lead to invasion and metastasis of tumor. So, one of the important future prospects is to address the inhibitors that act only on specific MMPs for the treatment of cancer.The smallest MMP identified to date, MMP-26 is of 261-amino-acid sequence. It includes only the minimal characteristic features of the MMP family: a signal peptide, a prodomain and a catalytic domain. MMP-26 is not only expressed in normal uterus, placenta, pellicula, glandular epithelial cells, vascular endothelial and endometrial stromal cells, but is widely expressed in malignant tumors from different sources as well as in diverse tumor cell lines. But so far, no reports of three-dimensional structure of MMP26, a lack of three-dimensional structure of human impede understanding of this enzyme.With the known crystal structure of metal -1 elastase and collagenase as a template, the use of homology modeling methods, to build a three-dimensional structure of cdMMP26 and after a series of assessment methods for evaluation, the results show that the structure of cdMMP26 modeling is reasonable. MMPs in the catalytic domain of protein sequence alignment was found, cdMMP26 protein 2 Zn ion-binding site is fairly conservative; 2 Ca ion-binding site is very conservative and one loci greater variability, combined with Ca ions do not fit. So the Ca ions in the three-dimensional structure of cdMMP26 rounding.Secondly, through the three-dimensional structural analysis of cdMMP26, useing AutoDock software, the use of molecular docking method, the interaction between cdMMPs and myricetin were discussed and found that binding free energies by computer cimulation in accordance with the enzyme kinetics of the experimental data, two data are in the same order of magnitude, the smaller error to prove that molecular docking techniques using computer simulation results are reliable.In addition, we have done the molecular docking with cdMMP26 and six traditional Chinese medicine which have better inhibition of MMPs, and found that luteolin, docking with cdMMP26 as traditional Chinese medicine monomer, had the lowest binding free energy with cdMMP26, the smallest Ki value, that is the best combination. The results of computer simulation of molecular docking analysis show that there is no interaction between Luteolin and cdMMP26 catalytic Zn ion binding cavity in the integration process, just have effective integration in the catalytic activity sites which dependent on zinc of sub-cdMMP26At the same time, with seven hydrogen bonds have cdMMP26, from the formation of hydrogen bonds can be seen on the location of these hydrogen bonds will be a very good position luteolin and fixed in the pockets of activity. Thus enhancing the combinative ability of compound, has a stronger inhibitory activity.Finally, we did molecular dynamics studies from AutoDock docking results, to analyzed the average of the results of molecular dynamics simulation done after 500 ps of the trajectory. Showe that the complex of cdMMP26 and luteolin, comparison of the stability of the fluctuation of energy, protein skeleton structure in molecular dynamics simulations are also relatively stable, and small molecule RMSD value of their relatively small range also shows cdMMP26 and luteolin binding site between the relatively stable.The use of molecular docking, molecular dynamics study of natural medicine drug screening for small molecule inhibition of cdMMP26 were discussed. Analysis the combination of model and possible binding sites, for structure designe that based on the specific matrix metalloproteinase inhibitors (MMPIs) provide useful information, in order to find a better help to the activity anti-cancer drugs.