Argonaute protein assisted drug discovery for miRNA-181c-5p and target gene ATM translation repression: a computational approach.

IF 3.9 2区化学 Q2 CHEMISTRY, APPLIED Molecular Diversity Pub Date : 2024-07-18 DOI:10.1007/s11030-024-10855-3

Harshita Tak, Jivanage Anirudh, Arpan Chattopadhyay, B Hemanth Naick

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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.

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针对 miRNA-181c-5p 和靶基因 ATM 翻译抑制的 Argonaute 蛋白辅助药物发现：一种计算方法。

miRNA 与 AGO 的种子区结合，促使人们探索能抵消 miRNA 对目标 mRNA 抑制的小分子。研究发现，这种miRNA-181c-5p在慢性创伤性脑病中上调，而慢性创伤性脑病是接触性运动和军事人员中普遍存在的一种神经退行性疾病。研究旨在找出能破坏 miRNA-181c-5p 和 ATM 之间 AGO 辅助环路形成，从而抑制 ATM 翻译的化合物。研究人员利用 DAVID 生物信息学工具，对三个常用数据库（DIANA-microT-CDS、miRDB、RNA22 和 TargetScan）中的靶基因进行了功能注释和聚类分析。利用 Haddock 服务器制作了 miRNA-181c-5p:ATM-AGO 复合物。通过三阶段对接法，利用 Glide XP 根据小分子与复合物的最高结合亲和力筛选出 2594 个小分子。利用 GROMACS（2023.2 版）进一步分析了前 5 种化合物（DB00674-Galantamine、DB00371-Meprobamate、DB00694-Daunorubicin、DB00837-Progabide 和 DB00851-Dacarbazine）在 miRNA-181c-5p:ATM-AGO 配体相互作用中的稳定性。因此，这些研究结果表明，这些分子具有促进 AGO 辅助抑制 ATM 基因翻译的潜力。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Molecular Diversity 化学-化学综合

CiteScore

7.30

自引率

7.90%

发文量

219

审稿时长

2.7 months

期刊介绍： Molecular Diversity is a new publication forum for the rapid publication of refereed papers dedicated to describing the development, application and theory of molecular diversity and combinatorial chemistry in basic and applied research and drug discovery. The journal publishes both short and full papers, perspectives, news and reviews dealing with all aspects of the generation of molecular diversity, application of diversity for screening against alternative targets of all types (biological, biophysical, technological), analysis of results obtained and their application in various scientific disciplines/approaches including: combinatorial chemistry and parallel synthesis; small molecule libraries; microwave synthesis; flow synthesis; fluorous synthesis; diversity oriented synthesis (DOS); nanoreactors; click chemistry; multiplex technologies; fragment- and ligand-based design; structure/function/SAR; computational chemistry and molecular design; chemoinformatics; screening techniques and screening interfaces; analytical and purification methods; robotics, automation and miniaturization; targeted libraries; display libraries; peptides and peptoids; proteins; oligonucleotides; carbohydrates; natural diversity; new methods of library formulation and deconvolution; directed evolution, origin of life and recombination; search techniques, landscapes, random chemistry and more;