Molecular Docking Study Of MMPs And MMP Inhibitors

With the development of theoretical and computational methods as well as molecular modeling technology, drug design came into a brand-new era, which mainly foucus on the rational drug design. The core of this concept is the discovery of new selective drugs against certain targets such as enzyme, receptor, ion channel and nucleic acid, based on some endogenous ligands or characteristic of the chemical structures of some natural products. The kernel of the methodology is the studies of the interactions between receptor and ligand. Rational drug design has become an active research area.The majority of cancer-related deaths result from tumor cell invasion metastasis. The processes of invasion and metastasis of tumor cells are complicated. The degradation of basement membrane and stromal tissue is essential for migration of endothelial cells which is needed to form new blood vessels and also critical for the entry and exit of tumor cells into existing blood vessels that are necessary for metastasis. The degradation of basement membrane and extracellular matrix (ECM) must be catalyzed by a series of proteinase which are a class of hydrolytic proteases named matrix metalloproteinases (MMPs).The relative highly expression of each MMP tends to improve tumor stage. Transfection of selected MMPs into cancer cells can increase the development of distant metastases in vivo. Regulation and inhibition of the activity of MMPs will control the invasion and metastasis of tumor cell, and thus prevent the tumor growth and progression. For these reasons, MMPs are considered to be key enzymes involved in angiogenesis and become an attractive therapeutic target.In this dissertation, molecular docking, molecular dynamics simulation and binding free energy calculation were used to investigate the binding modes and drug resistance of MMPs and their inhibitors. Analyzed of the MMPs'three-dimensional structural, the software of AutoDock and GROMACS were used to find the possible binding sites. These studies will be helpful for design and discovery of new active cancer drugs.Based on the analysis of the results of computer simulation, we found that there was no interaction between the pyrogallic acid and the catalytic zinc. But its binding site was in the S1'pocket. Meanwhile, the simulation combined with the free enzyme kinetics is in concordance to the experimental data, which suggests these two results were in the same order of magnitude with little error. Therefore these results based on the structure of MMPs and MMPIs will provide useful information for the drug design.