Investigation Into Drug Design And Mechanism Of Key Target In Pathogen

Computer-aided Drug Design(CADD) is widely used in the field of drug research as an important theoretical tool. In drug discovery, Molecular Docking, Molecular Dynamics and Quantum Mechanics/Molecular Mechanics are valid methods for CADD. Molecular docking is commonly used as a tool of virtual screening,which both promoting the hit rate and reducing the period. Molecular Dynamics, which is a promising method in demonstrating the relationship between structure and biological function for biomacromolecule, could simulate dynamic behavior for protein to reveal important characteristic and function for biomacromolecule systems at atomic-level. Combined use of quantum mechanics and molecular mechanics(QM/MM) is the most popular method to investigate enzyme catalysis mechanics with treating the key catalytic active site with quantum method and additional section with molecular method, Which not only take advantages of accuracy of quantum method but also reduce the research period.In this thesis, our research mainly focuses on key targets of two pathogens, namely protein arginine methylation transferase I (PRMT1)and lipoteichoic acid systhase (LtaS), to conduct drug design and study of mechanism by adopting aforementioned methods.Staphylococcus aureus affection had been a fatal pathogen threaten to human health, the conditions became server especially when superbug MRS A was detected. As had been revealed, LtaS (polyglycerol-phosphate lipoteichoic acid syhthase) as the vital enzyme for the synthesizing of polyglycerol-phosphate lipoteichoic acid (LTA), is a ideal potential antimicrobial target for drug design. Investigating into the catalysis mechanics about LtaS is of vital significance to the design of inhibitors. In this thesis we presented a theoretical study on LtaS and the activity of active pocket. Binary complex models were constructed based on molecular docking and verified by MD simulation. Through QM/MM calculations, the typical potential energy profile were dipected after abstracting appropriate conformation from the MD trajectory. By substituting Mn2+ with Ca2+、Zn2+ respectively, we also discussed the reason why they show different activity.Protein arginine methylation(PRMT) is a posttranslational modification critical for a variety of biological processes.PRMT1 is the primarily Protein arginine methylation enzyme in mammals whose abnormal could induce abnormal in related pathway, resulting in a series of cancer such as breast cancer,gastric cancer and lymphoma caner. We employed multiple structure-based drug design approaches to screen related database based on the overall protein structure modeling on the crystal structure, and in the final we got several bioactive compound in which two molecule having good cellular activity. Finally we analysis the SAR of docked conformation, which lay foundation of further modification for the candidate compounds.