m7G-RNA 写入器 METTL1 的小分子抑制剂

IF 3.8 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY ACS Bio & Med Chem Au Pub Date : 2023-12-12 DOI:10.1021/acsbiomedchemau.3c00030
Francesco Nai, Maria Paula Flores Espinoza, Annalisa Invernizzi, Pablo Andrés Vargas-Rosales, Olga Bobileva, Marcin Herok and Amedeo Caflisch*, 
{"title":"m7G-RNA 写入器 METTL1 的小分子抑制剂","authors":"Francesco Nai,&nbsp;Maria Paula Flores Espinoza,&nbsp;Annalisa Invernizzi,&nbsp;Pablo Andrés Vargas-Rosales,&nbsp;Olga Bobileva,&nbsp;Marcin Herok and Amedeo Caflisch*,&nbsp;","doi":"10.1021/acsbiomedchemau.3c00030","DOIUrl":null,"url":null,"abstract":"<p >We discovered the first inhibitors of the m7G-RNA writer METTL1 by high-throughput docking and an enzymatic assay based on luminescence. Eleven compounds, which belong to three different chemotypes, show inhibitory activity in the range 40–300 μM. Two adenine derivatives identified by docking have very favorable ligand efficiency of 0.34 and 0.31 kcal/mol per non-hydrogen atom, respectively. Molecular dynamics simulations provide evidence that the inhibitors compete with the binding of the cosubstrate <i>S</i>-adenosyl methionine to METTL1. We also present a soakable crystal form that was used to determine the structure of the complex of METTL1 with sinefungin at a resolution of 1.85 Å.</p>","PeriodicalId":29802,"journal":{"name":"ACS Bio & Med Chem Au","volume":null,"pages":null},"PeriodicalIF":3.8000,"publicationDate":"2023-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acsbiomedchemau.3c00030","citationCount":"0","resultStr":"{\"title\":\"Small-Molecule Inhibitors of the m7G-RNA Writer METTL1\",\"authors\":\"Francesco Nai,&nbsp;Maria Paula Flores Espinoza,&nbsp;Annalisa Invernizzi,&nbsp;Pablo Andrés Vargas-Rosales,&nbsp;Olga Bobileva,&nbsp;Marcin Herok and Amedeo Caflisch*,&nbsp;\",\"doi\":\"10.1021/acsbiomedchemau.3c00030\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p >We discovered the first inhibitors of the m7G-RNA writer METTL1 by high-throughput docking and an enzymatic assay based on luminescence. Eleven compounds, which belong to three different chemotypes, show inhibitory activity in the range 40–300 μM. Two adenine derivatives identified by docking have very favorable ligand efficiency of 0.34 and 0.31 kcal/mol per non-hydrogen atom, respectively. Molecular dynamics simulations provide evidence that the inhibitors compete with the binding of the cosubstrate <i>S</i>-adenosyl methionine to METTL1. We also present a soakable crystal form that was used to determine the structure of the complex of METTL1 with sinefungin at a resolution of 1.85 Å.</p>\",\"PeriodicalId\":29802,\"journal\":{\"name\":\"ACS Bio & Med Chem Au\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":3.8000,\"publicationDate\":\"2023-12-12\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://pubs.acs.org/doi/epdf/10.1021/acsbiomedchemau.3c00030\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"ACS Bio & Med Chem Au\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://pubs.acs.org/doi/10.1021/acsbiomedchemau.3c00030\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"BIOCHEMISTRY & MOLECULAR BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"ACS Bio & Med Chem Au","FirstCategoryId":"1085","ListUrlMain":"https://pubs.acs.org/doi/10.1021/acsbiomedchemau.3c00030","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
引用次数: 0

摘要

我们通过高通量对接和基于发光的酶测定发现了 m7G-RNA 作家 METTL1 的首个抑制剂。属于三种不同化学类型的 11 种化合物显示出 40-300 μM 的抑制活性。通过对接确定的两种腺嘌呤衍生物具有非常有利的配体效率,每个非氢原子的配体效率分别为 0.34 和 0.31 kcal/mol。分子动力学模拟证明,这些抑制剂与共底物 S-腺苷蛋氨酸与 METTL1 的结合存在竞争。我们还展示了一种可浸泡的晶体形式,用于确定 METTL1 与正鱼藤素复合物的结构,分辨率为 1.85 Å。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

摘要图片

摘要图片

查看原文
分享 分享
微信好友 朋友圈 QQ好友 复制链接
本刊更多论文
Small-Molecule Inhibitors of the m7G-RNA Writer METTL1

We discovered the first inhibitors of the m7G-RNA writer METTL1 by high-throughput docking and an enzymatic assay based on luminescence. Eleven compounds, which belong to three different chemotypes, show inhibitory activity in the range 40–300 μM. Two adenine derivatives identified by docking have very favorable ligand efficiency of 0.34 and 0.31 kcal/mol per non-hydrogen atom, respectively. Molecular dynamics simulations provide evidence that the inhibitors compete with the binding of the cosubstrate S-adenosyl methionine to METTL1. We also present a soakable crystal form that was used to determine the structure of the complex of METTL1 with sinefungin at a resolution of 1.85 Å.

求助全文
通过发布文献求助,成功后即可免费获取论文全文。 去求助
来源期刊
ACS Bio & Med Chem Au
ACS Bio & Med Chem Au 药物、生物、化学-
CiteScore
4.10
自引率
0.00%
发文量
0
期刊介绍: ACS Bio & Med Chem Au is a broad scope open access journal which publishes short letters comprehensive articles reviews and perspectives in all aspects of biological and medicinal chemistry. Studies providing fundamental insights or describing novel syntheses as well as clinical or other applications-based work are welcomed.This broad scope includes experimental and theoretical studies on the chemical physical mechanistic and/or structural basis of biological or cell function in all domains of life. It encompasses the fields of chemical biology synthetic biology disease biology cell biology agriculture and food natural products research nucleic acid biology neuroscience structural biology and biophysics.The journal publishes studies that pertain to a broad range of medicinal chemistry including compound design and optimization biological evaluation molecular mechanistic understanding of drug delivery and drug delivery systems imaging agents and pharmacology and translational science of both small and large bioactive molecules. Novel computational cheminformatics and structural studies for the identification (or structure-activity relationship analysis) of bioactive molecules ligands and their targets are also welcome. The journal will consider computational studies applying established computational methods but only in combination with novel and original experimental data (e.g. in cases where new compounds have been designed and tested).Also included in the scope of the journal are articles relating to infectious diseases research on pathogens host-pathogen interactions therapeutics diagnostics vaccines drug-delivery systems and other biomedical technology development pertaining to infectious diseases.
期刊最新文献
Issue Editorial Masthead Issue Publication Information New Catalytic Residues and Catalytic Mechanism of the RNase T1 Family New Catalytic Residues and Catalytic Mechanism of the RNase T1 Family Design, Synthesis, and Biological Evaluation of Darunavir Analogs as HIV-1 Protease Inhibitors
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
现在去查看 取消
×
提示
确定
0
微信
客服QQ
Book学术公众号 扫码关注我们
反馈
×
意见反馈
请填写您的意见或建议
请填写您的手机或邮箱
已复制链接
已复制链接
快去分享给好友吧!
我知道了
×
扫码分享
扫码分享
Book学术官方微信
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术
文献互助 智能选刊 最新文献 互助须知 联系我们:info@booksci.cn
Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。
Copyright © 2023 Book学术 All rights reserved.
ghs 京公网安备 11010802042870号 京ICP备2023020795号-1