虚拟筛选与蛋白降解在TRPC5调节剂发现设计中的实践
文献类型：学位论文
| ; | |
| 作者 | 刘斌 |
| 答辩日期 | 2021-05 |
| 导师 | 左之利 |
| 英文摘要 | As a member of the transient receptor potential (TRP) cation channel family, TRPC5 plays a pivotal role in mediating extracellular Na+ and Ca2+ influx. In addition, it is also involved in the regulation of various central nervous system diseases including anxiety, depression, epilepsy, memory, addiction, and pain. But up to now, there is no enough in-depth and comprehensive research on the functional regulation of TRPC5 at the cell or tissue level. There are a few types of small molecule inhibitors of TRPC5 reported, and they have some disadvantages, such as poor specificity and poor druggability. In the first chapter, this thesis respectively reviewed the research progress of TRPC5 ion channel-related diseases and their inhibitors, proteolytic targeted chimera (PROTACs) technology, and lysosomal targeted chimera (LYTACs) technology research progress, respectively. In the second chapter of this paper, hTRPC5 was used as the target protein to carry out virtual screening based on the receptor structure using CADD method, combined with the evaluation of biological activity. Finally, a hit of LB-9 with a good inhibitory effect on hTRPC5 was found. At the beginning of this research work, the three-dimensional crystal structure of human TRPC5 (hTRPC5) protein has not been successfully resolved and the experimental information of the key amino acid residues of the small molecule binding site is not clear. We established the hTRPC5 three-dimensional structure based on the homology model, and then the combining structural biology and amino acid conservation analysis was used to make a preliminary prediction of the small molecule binding site. Next, we apply different precision molecular docking programs (LibDock, GOLD, SYBYL) to perform gradient virtual screening against Specs commercial small molecule compound library. The combine cluster analysis, interaction mode analysis, molecular dynamics simulation, and complex binding free energy Calculation, energy decomposition were applied to obtain 12 hits for purchase. The subsequent evaluation of cellular calcium flow activity were carried. The results showed that the small molecule LB-9 has a good inhibitory effect against hTRPC5 (IC50 = 4.45 μM). The proteolysis-targeting chimeras (PROTACs) method is a new method of drug discovery developed in recent years. Based on this method, in the third chapter of this paper, we used TRPC5 selective inhibitor AC1903 and non-selective inhibitor M084 as target protein ligands to design and synthesize two series of TRPC5 small molecule degradation agents with different carbon chain lengths (15 Compounds) to study the effects of different types of inhibitors as target protein ligands and different length Linkers on the degradation activity of the target protein. At this stage, the activity evaluation is still in progress. In the fourth chapter of this paper, based on the lysosome-targeting chimeras (LYTACs) method, we designed and synthesized 8 TRPC5 small molecule degrad |
| 源URL | [http://ir.kib.ac.cn/handle/151853/74609]  |
| 专题 | 昆明植物研究所_昆明植物所硕博研究生毕业学位论文 |
| 推荐引用方式 GB/T 7714 | 刘斌. 虚拟筛选与蛋白降解在TRPC5调节剂发现设计中的实践, Practice of Virtual Screening and Protein Degradation in the Discovery and Design of TRPC5 Regulators[D]. 2021. |
入库方式： OAI收割
来源：昆明植物研究所
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