Abstract：
The miRNA binds to AGO\'s seed region, prompting the exploration of small molecules that can offset miRNA repression of target mRNA. This miRNA-181c-5p was found to be upregulated in the chronic traumatic encephalopathy, a prevalent neurodegenerative disease in contact sports and military personals. The research aimed to identify compounds that disrupt the AGO-assisted loop formation between miRNA-181c-5p and ATM, consequently repressing the translation of ATM. Target genes from commonly three databases (DIANA-microT-CDS, miRDB, RNA22 and TargetScan) were subjected to functional annotation and clustering analysis using DAVID bioinformatics tool. Haddock server were employed to make miRNA-181c-5p:ATM-AGO complex. A total of 2594 small molecules were screened using Glide XP based on their highest binding affinity towards the complex, through a three-phase docking approach. The top 5 compounds (DB00674-Galantamine, DB00371-Meprobamate, DB00694-Daunorubicin, DB00837-Progabide, and DB00851-Dacarbazine) were further analyzed for stability in the miRNA-181c-5p:ATM-AGO-ligand complex interaction using GROMACS (version 2023.2). Hence, these findings suggest that these molecules hold potential for facilitating AGO-assisted repression of ATM gene translation.
摘要：
miRNA与AGO的种子区结合，提示探索可以抵消miRNA抑制靶mRNA的小分子。发现这种miRNA-181c-5p在慢性创伤性脑病中上调，接触性运动和军事人员中普遍存在的神经退行性疾病。该研究旨在鉴定破坏miRNA-181c-5p和ATM之间AGO辅助环形成的化合物，因此抑制了ATM的翻译。通常来自三个数据库的靶基因(DIANA-microT-CDS，miRDB,RNA22和TargetScan）使用DAVID生物信息学工具进行功能注释和聚类分析。采用Haddock服务器制备miRNA-181c-5p:ATM-AGO复合物。基于它们对复合物的最高结合亲和力，使用GlideXP筛选了总共2594个小分子，通过三相对接的方式。前5种化合物(DB00674-加兰他敏,DB00371-甲氨酯,DB00694-柔红霉素,DB00837-Progbeints,和DB00851-达卡巴嗪）使用GROMACS（版本2023.2）进一步分析了miRNA-181c-5p：ATM-AGO-配体复合物相互作用中的稳定性。因此，这些发现表明,这些分子具有促进AGO辅助抑制ATM基因翻译的潜力.
