Drug Molecular Computer-aided Theoretical Simulation And Molecular Design

Traditional drug discovery is not only time-consuming but also randomness and blindness, so it is difficult to find new drugs fastly and efficiently. With the continuous development of computer science, computational chemistry has become a rapid development discipline. The computer aided molecular design method is gradually mature, which has become one of the main approaches of drug molecular design. Various molecular simulation methods have been applied in the design and development of therapeutic drugs, such as quantitative structure-activity relationship (QSAR), molecular docking, and molecular dynamics simulation. First of all, this dissertation used quantitative structure-activity relationship to study HIV-1(Human Immunodeficiency Virus) inhibitors, GPR55(G-protein Receptor55) inhibitors and TLR8(Toll-like Receptor8) agonists, established some reliable and stable models, and evaluated those models. In addition, molecular docking and molecular dynamics were used to research HIV-1inhibitors with HIV-1protease and TLR8agonists with TLR8receptor, and got the action mode between drug molecules and proteins, which could provide theoretical guidance for further study.First chapter of the thesis mainly introduced the background of research methods and progress of the theory of simulation. Theory methods mainly include:based on SMILES (Simplified Molecular Input Line Entry System) and based on the molecular descriptors of two-dimensional quantitative structure-activity relationship (2D-QSAR), three-dimensional quantitative structure activity relationship (3D-QSAR), molecular docking and molecular dynamics. At last, the main contents of this thesis were introduced briefly.In the second chapter, quantitative structure-activity relationship, molecular docking and molecular dynamics methods were used to study HIV-1inhibitors. Firstly, molecular descriptors and SMILES codes were used to establish reliable models, and the factors of influence on the compound’s activity were discussed in the multiple linear regression (MLR) model. Secondly, molecular docking and molecular dynamics simulation were utilized to study the interactions between HIV-1inhibitors and HIV-1protein (1BDR), thereby got the action mode for further understanding the mechanism of action.In the third chapter, the traditional MLR, the new SMILES-based method, and CoMFA (Comparative Molecular Field Analysis) and CoMSIA (Comparative Molecular Similarity Index Analysis) of3D-QSAR were applied to study GPR55antagonists. Several reasonable computable models were built, and the factors that influence the activities of the compounds were discussed. At last, these models’ prediction ability validated by using various validation methods for the test set. Besides, twenty-eight compounds without clear activities were tested by the established models and six new potential inhibitors with higher predicted activities were designed.In the fourth chapter, SMILES-based method, CoMFA and CoMSIA were used to study the TLR8agonists. Several reliable models were established, and those models were verified. The factors that influence the activities of the drugs were got through analyzing the CoMFA and CoMSIA contour maps, which provide theoretical guidance for designing new drugs. Finally, using molecular docking and molecular dynamics simulation, interactions between the TLR8agonists and TLR8receptors (3W3K) were studied.