Theoretical Studies On The Potency And Selectivity Of Matrix Metalloproteinase Inhibitors And The Reaction Mechanism Catalyzed By Chalcone Synthase

In recent years, along with the development of molecule mechanics, dynamics, and quantum mechanics theories, and the progress of calculator technique, molecule simulations have already become a main research method in the fields of biology and medical science to analyze the interactions between receptor and ligand, and describe protein biochemistry mechanism.In our thesis, molecule mechanics, dynamics, and quantum mechanics methods were used to theoretically study the potency and selectivity of matrix metalloproteinases (MMPs) inhibitors and the reaction mechanism catalyzed by chalcone synthase (CHS). The main results are summarized as follows:1. Theoretical studies on potency and selectivity of novel non-peptide inhibitors of MMP-1 and MMP-3To investigate the binding modes between the novel non-peptide inhibitors (Pyrogallic acid and Myricetin) and MMPs (MMP-1 and MMP-3), molecular docking studies were performed. The results indicate that Myricetin is more potent than Pyrogallic acid due to the P1'group at C13 atom of Myricetin, which interacts with S1'pocket of MMPs and thus contributes a lot to the binding affinity. The reasons for that Myricetin is more selective towards MMP-1 than MMP-3 may include the positions of zinc binding group (ZBG), the number of hydrogen bonds, and the interactions between P1'and S1'. Furthermore, the hydroxyl acts as a relatively weak ZBG and the meta-double-hydroxyl mode may be conserved when inhibitors of this kind bind to MMPs. Quantum chemistry calculation results show that inhibitors can bind to the catalytic zinc ion of MMPs with ZBG in a monodentate way.2. Theoretical studies on potency and selectivity of novel non-peptide inhibitors of MMP-2 and MMP-9Molecular docking studies were performed to investigate the binding modes between the novel non-peptide inhibitors (Myricetin and Kaempferol) and MMPs (MMP-2 and MMP-9). The results indicate that the completely different binding modes, resulting from that Myricetin owns two more side hydroxyls on benzene ring, lead to that Myricetin is more potent than Kaempferol; in aspect of selectivity, the similar binding modes in each complex pair (m-MMP2 and m-MMP9, k-MMP2 and k-MMP9) make the non-obvious selectivities of inhibitors. Moreover, the hydroxyl acts as a relatively weak ZBG and the meta-double-hydroxyl mode may be conserved. Quantum chemistry calculation results show again that inhibitors can bind to the catalytic zinc ion of MMPs with ZBG in a monodentate way.3. Theoretical studies on the reaction mechanism catalyzed by CHSThe chalcone formation catalyzed by CHS from P-coumaroyl-CoA and Malonyl-CoA were theoretically studied. The calculation results indicate that in loading step, the reaction proceeds via a tetrahedral intermediate without transition state (TS); in decarboxylation step, the reaction proceeds via a TS and is sensitive to the environment; in elongation step, the reaction proceeds via a tetrahedral TS. The calculation results greatly support and complement the reaction mechanism proposed on experiment.