Insight into the Mechanism of 17β-Hydroxysteroid Dehydrogenase Type 3 Inhibition by the Androsterone Derivative RM-532-105

Q4 Pharmacology, Toxicology and Pharmaceutics
P. Stephen, J. Roy, R. Maltais, D. Poirier
{"title":"Insight into the Mechanism of 17β-Hydroxysteroid Dehydrogenase Type 3 Inhibition by the Androsterone Derivative RM-532-105","authors":"P. Stephen, J. Roy, R. Maltais, D. Poirier","doi":"10.2174/1573408016999200729110245","DOIUrl":null,"url":null,"abstract":"\n\nThe last step in the production of androgen testosterone from 4-androstene-\n3,17-dione (4-dione) in testis involves the 17β-hydroxysteroid dehydrogenase type 3 (17β-HSD3).\nBlocking this microsomal enzyme with an inhibitor would lower the level of testosterone and, consequently,\ncould be an approach for the treatment of androgen-dependent diseases. RM-532-105 was\ndeveloped as a steroidal inhibitor of 17β-HSD3, but its mechanism of action is not yet known.\n\n\n\nTo identify potential binding sites of the 17β-HSD3 substrate 4-dione, cofactor NADPH,\nas well as inhibitor RM-532-105.\n\n\n\nSince there is no crystal structure of 17β-HSD3 available, complexed or not with a ligand,\na homology model was prepared followed by molecular docking, and enzymatic assay experiments\nwere performed.\n\n\n\nTransfected LNCaP prostate cancer cells were used as a source of 17β-HSD3 activity for the\ntransformation of 4-dione into testosterone in the presence of varying concentrations of a substrate, a\ncofactor or an inhibitor. Molecular modeling experiments and enzymatic assays with these cells suggest\na competitive action of RM-532-105 with the cofactor and a non-competitive action with the\nsubstrate 4-dione.\n\n\n\nThese results allow the selection of one inhibitor orientation in the enzyme binding site,\nfrom the two possibilities predicted by the docking experiments, and appear to be in agreement with\nprevious structure-activity relationships.\n","PeriodicalId":35405,"journal":{"name":"Current Enzyme Inhibition","volume":null,"pages":null},"PeriodicalIF":0.0000,"publicationDate":"2020-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"2","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Current Enzyme Inhibition","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.2174/1573408016999200729110245","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q4","JCRName":"Pharmacology, Toxicology and Pharmaceutics","Score":null,"Total":0}
引用次数: 2

Abstract

The last step in the production of androgen testosterone from 4-androstene- 3,17-dione (4-dione) in testis involves the 17β-hydroxysteroid dehydrogenase type 3 (17β-HSD3). Blocking this microsomal enzyme with an inhibitor would lower the level of testosterone and, consequently, could be an approach for the treatment of androgen-dependent diseases. RM-532-105 was developed as a steroidal inhibitor of 17β-HSD3, but its mechanism of action is not yet known. To identify potential binding sites of the 17β-HSD3 substrate 4-dione, cofactor NADPH, as well as inhibitor RM-532-105. Since there is no crystal structure of 17β-HSD3 available, complexed or not with a ligand, a homology model was prepared followed by molecular docking, and enzymatic assay experiments were performed. Transfected LNCaP prostate cancer cells were used as a source of 17β-HSD3 activity for the transformation of 4-dione into testosterone in the presence of varying concentrations of a substrate, a cofactor or an inhibitor. Molecular modeling experiments and enzymatic assays with these cells suggest a competitive action of RM-532-105 with the cofactor and a non-competitive action with the substrate 4-dione. These results allow the selection of one inhibitor orientation in the enzyme binding site, from the two possibilities predicted by the docking experiments, and appear to be in agreement with previous structure-activity relationships.
雄酮衍生物RM-532-105抑制17β-羟基类固醇脱氢酶3型的机制
从睾丸中的4-雄烯-3,17-二酮(4-酮)产生雄激素睾酮的最后一步涉及17β-羟基类固醇脱氢酶3型(17β-HSD3)。用抑制剂阻断这种微粒体酶会降低睾酮水平,因此可能是治疗雄激素依赖性疾病的一种方法。RM-532-105是一种17β-HSD3的甾体抑制剂,但其作用机制尚不清楚。为了鉴定17β-HSD3底物4-二酮、辅因子NADPH以及抑制剂RM-532-105的潜在结合位点。由于17β-HDD3没有可用的晶体结构,无论是否与配体络合,我们制备了同源模型,然后进行了分子对接,并进行了酶分析实验。使用转染的LNCaP前列腺癌症细胞作为17β-HSD3活性的来源,在存在不同浓度的底物、辅助因子或抑制剂的情况下,将4-二酮转化为睾酮。分子建模实验和对这些细胞的酶分析表明,RM-532-105与辅因子具有竞争作用,与底物4-二酮具有非竞争作用。这些结果允许从对接实验预测的两种可能性中选择酶结合位点中的一种抑制剂取向,并且似乎与以前的结构-活性关系一致。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
求助全文
约1分钟内获得全文 求助全文
来源期刊
Current Enzyme Inhibition
Current Enzyme Inhibition Pharmacology, Toxicology and Pharmaceutics-Drug Discovery
CiteScore
1.30
自引率
0.00%
发文量
30
期刊介绍: Current Enzyme Inhibition aims to publish all the latest and outstanding developments in enzyme inhibition studies with regards to the mechanisms of inhibitory processes of enzymes, recognition of active sites, and the discovery of agonists and antagonists, leading to the design and development of new drugs of significant therapeutic value. Each issue contains a series of timely, in-depth reviews written by leaders in the field, covering a range of enzymes that can be exploited for drug development. Current Enzyme Inhibition is an essential journal for every pharmaceutical and medicinal chemist who wishes to have up-to-date knowledge about each and every development in the study of enzyme inhibition.
×
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
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
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 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术官方微信