Studies On The Interactions Of ALR2 And HCV NS5B Polymerase With Drugs By 3D-QSAR And Molecular Docking

Protein, made up of amino acids, is one of the basic materials of life. It plays a vital role in a variety of biological phenomena and life processes. Meanwhile, there are also many kinds of small organic molecules with different physiological functions in organisms, which are very important to the control and adjustment of regular function. Therefore, the binding of small molecule and the target protein is one of the most basic interactions of life. With the rapid development of molecular biology and organic synthesis technology, more and more scientists dedicate to the studies of small molecule-protein interaction with the purpose of investigating the essence of life at the molecular level. In this paper, we systematically performed theoretical research focused on the issues of the binding mode of small molecule and protein, as well as 3D-QSAR based drug design. Many valuable results have been obtained, which were mainly summarized as follows:In this paper, we chose a series of inhibitors of Aldose Reductase-ALR2 and HCV NS5B polymerase to study 3D QSAR and interaction mechanism using CoMFA and CoMSIA. Thus, we obtained structural characteristics of these inhibitors, QSAR, binding sites and possible docking modes. In addition, as for the HCV NS5B polymerase, based on the results of 3D-QSAR and docking, we designed some new inhibitors with high activity and provided useful theoretical information for experimental researchers.Four chapters are included in this dissertation.Thelstchapter is introduction.This part introduced the present situation and development history of studies on Aldose Reductase-ALR2 and HCV NS5B polymerase inhibitors, concluded the possible inhibition mechanism, the present situation, and the theoretical development, and described the significance of QSAR, interaction mechanism, and molecular design.The theoretical foundation and calculational methods are presented in the 2nd chapter.The basic principles and methods of quantum chemistry 3D-QSAR molecule docking analysis are systematically and briefly introduced. The 3rd chapter,3D-QSAR and molecular docking studies on indoleacetic aldose reductase inhibitors. Aldose reductase-ALR2 is an important glucose-converting enzyme, and the overactivity of it is believed to be one of the primary causes that lead to the onset of diabetic complications. Indoleacetic aldose reductase inhibitors are a compounds with biological activities. Comparative Molecular Field Analysis (CoMFA) and Comparative Molecular Similarity Indices Analysis (CoMSIA) methods were used to investigate indoleacetic inhibitors of aldose reductase (ALR2). A good 3D-QSAR model with significant statistical quality and excellent predictive ability was established.The possible binding sites were also obtained.The 3D-QSAR resules were found in good agreement with the structural characteristics of the corresponding binding sites.These resules further show the reliability of the established 3D-QSAR model. The results in this chapter offer some new insights on understanding the inhibition mechanism of this kind of inhibitors and may provide useful information for understanding the structure-activity relationship of indoleacetic compounds and designing new inhibitors.The 4th chapter,3D-QSAR studies on benzimidazole derivatives with inhibitory activity to hepatitis C virus NS5B polymerase.3D-QSAR analysis as the most common method of drug design has the advantages of high predictive ability, precise model with intuition and so on. In this paper, Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) of 53 novel benzimidazole HCV NS5B polymerase inhibitors were performed based on both ligand-based and receptor-based alignments. Calculations found that ligand-based model showed better statistical characteristics. Models were validated using an external test set of 12 compounds with structural diversity. Though the CoMFA model has the best predictive ability, both the ligand-based CoMFA and CoMSIA models were proved to be reliable and predictive. Molecular docking studies showed that such derivatives interact with NS5B active pocket mainly through hydrogen bonds and hydrophobic interactions. The 3D-QSAR resules were found in good agreement with the structural characteristics of the corresponding binding sites. Based on the analysis of CoMFA maps and binding mode, some new benzimidazole derivatives which showed higher predicted pICso values were designed. The results provide insight for designing aspects of this class of NS5B inhibitors for better activity.