Theoretical Prediction Of Protein-drug Binding Structure For 3HNRase And FBPase By DOX Method

The accurate acquisition of biomacromolecule-ligand binding conformation is the most important condition for the study of the ground state and the excited state to obtain properties of ligand molecules in biological macromolecules, and is particularly important in drug design which is based on receptor structure. Molecular docking is the most commonly used technique in drug design, which can quickly predict the binding pattern of ligand in protein receptor binding sites and the strength of binding ability.However, because of its calculation principle, there is still a shortcoming in the accuracy of the prediciton. In recent years, due to the high precision of quantum mechanics in predicting the binding energy of drug proteins, it has been widely used in drug design,especially the density functional method(DFT) based on the first principle. In the calculation of biological system, the density functional method is also faced with the huge challenge of high computational complexity while improving the computational accuracy. In 1976, Warshel and Levitt proposed the QM / MM method, which effectively solved the problem. In 1996, the ONIOM method proposed by Keiji Morokuma was a popular QM / MM method. For the biological system, the ONIOM method not only effectively improve the accuracy, also reduces the computational effort to a certain extent,but is still limited by the size of the drug-protein complexity. In 2010, Xu Xin's group proposed an extended ONIOM hierarchical method (XO method) based on the principle of expulsion in the molecular fragmentation method and the extrapolated form of the ONIOM method. This method can effectively increase the computational accuracy of the QM region and reduce the computational complexity.In this paper, molecular docking, ONIOM method, a semiempirical quantum chemistry program MOPAC, and XO method are used to propose a new hybrid computational method, DOX, toward predicting the accurate binding structures, which is the preprequisite for all protein-drug complexes, and methods were used in Trihydroxynaphthalene reductase (3HNR) system to verify the accuracy. In addition, the binding conformation of two sites (substrate and allosteric sites) of human fructose-1,6-bisphosphatase (Hu-FBPase) with the series of drug molecules was calculated and predicted by DOX method to provide new ideas for the further design and synthesis of new drug molecules. The following work mainly carried out:1.The first generation DOX test: based on the small molecular conformation in crystal structure (Redocking). The four crystal complexes (1DOH, 1YBV,1G0N,1G0O)for 3hnrase were calculated by DOX method..2.The first generation and the second generation DOX test: based on the Confort method to build molecular docking starting conformation. In the first generation DOX method, the 1DOH, 1YBV, 1GON and 1G0O were also calculated and tested at two levels:the host protein and the same protein. And the test was more stringent and realistic.3 The first generation DOX method was used to calculate and predict the structure of HS29, HS45 and HS16 in the substrate sites and transformation site of human liver fructose-1, 6-bisphosphatase (Hu-FBPase). We can get much information from the protein-drug structure for the further design. In addition,, it's helpful to explore the mechanism.