增强采样模拟中的 CYP17A1 二级结合位点

IF 5.6 2区化学 Q1 CHEMISTRY, MEDICINAL Journal of Chemical Information and Modeling Pub Date : 2024-09-26 DOI:10.1021/acs.jcim.4c01293

Tomasz M. Wróbel, Damian Bartuzi, Agnieszka A. Kaczor

{"title":"增强采样模拟中的 CYP17A1 二级结合位点","authors":"Tomasz M. Wróbel, Damian Bartuzi, Agnieszka A. Kaczor","doi":"10.1021/acs.jcim.4c01293","DOIUrl":null,"url":null,"abstract":"Androgens like testosterone and dihydrotestosterone play a key role in prostate cancer progression, making the enzyme CYP17A1, essential for androgen synthesis, a crucial therapeutic target. Recent studies have revealed electron density at the substrate entry channel, suggesting the presence of a secondary binding site. In this study, we calculated the binding free energy landscape of known ligands at this site using Funnel Metadynamics. Our results characterize this binding site and indicate that nonheme-interacting ligands could effectively bind to CYP17A1, providing a novel approach to the design of CYP17A1 inhibitors.","PeriodicalId":44,"journal":{"name":"Journal of Chemical Information and Modeling ","volume":null,"pages":null},"PeriodicalIF":5.6000,"publicationDate":"2024-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Secondary Binding Site of CYP17A1 in Enhanced Sampling Simulations\",\"authors\":\"Tomasz M. Wróbel, Damian Bartuzi, Agnieszka A. Kaczor\",\"doi\":\"10.1021/acs.jcim.4c01293\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"Androgens like testosterone and dihydrotestosterone play a key role in prostate cancer progression, making the enzyme CYP17A1, essential for androgen synthesis, a crucial therapeutic target. Recent studies have revealed electron density at the substrate entry channel, suggesting the presence of a secondary binding site. In this study, we calculated the binding free energy landscape of known ligands at this site using Funnel Metadynamics. Our results characterize this binding site and indicate that nonheme-interacting ligands could effectively bind to CYP17A1, providing a novel approach to the design of CYP17A1 inhibitors.\",\"PeriodicalId\":44,\"journal\":{\"name\":\"Journal of Chemical Information and Modeling \",\"volume\":null,\"pages\":null},\"PeriodicalIF\":5.6000,\"publicationDate\":\"2024-09-26\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of Chemical Information and Modeling \",\"FirstCategoryId\":\"92\",\"ListUrlMain\":\"https://doi.org/10.1021/acs.jcim.4c01293\",\"RegionNum\":2,\"RegionCategory\":\"化学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"CHEMISTRY, MEDICINAL\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Chemical Information and Modeling ","FirstCategoryId":"92","ListUrlMain":"https://doi.org/10.1021/acs.jcim.4c01293","RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CHEMISTRY, MEDICINAL","Score":null,"Total":0}

引用次数: 0

摘要

睾酮和双氢睾酮等雄性激素在前列腺癌的发展过程中起着关键作用，这使得雄性激素合成所必需的 CYP17A1 酶成为重要的治疗靶点。最近的研究揭示了底物进入通道处的电子密度，表明存在二级结合位点。在本研究中，我们利用漏斗元动力学计算了已知配体在该位点的结合自由能图谱。我们的研究结果描述了该结合位点的特征，并表明非血红素相互作用配体可以有效地与 CYP17A1 结合，为设计 CYP17A1 抑制剂提供了一种新方法。

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

查看原文

微信好友朋友圈 QQ好友复制链接

本刊更多论文

Secondary Binding Site of CYP17A1 in Enhanced Sampling Simulations

Androgens like testosterone and dihydrotestosterone play a key role in prostate cancer progression, making the enzyme CYP17A1, essential for androgen synthesis, a crucial therapeutic target. Recent studies have revealed electron density at the substrate entry channel, suggesting the presence of a secondary binding site. In this study, we calculated the binding free energy landscape of known ligands at this site using Funnel Metadynamics. Our results characterize this binding site and indicate that nonheme-interacting ligands could effectively bind to CYP17A1, providing a novel approach to the design of CYP17A1 inhibitors.

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

Journal of Chemical Information and Modeling 化学-化学综合

CiteScore

9.80

自引率

10.70%

发文量

529

审稿时长

1.4 months

期刊介绍： The Journal of Chemical Information and Modeling publishes papers reporting new methodology and/or important applications in the fields of chemical informatics and molecular modeling. Specific topics include the representation and computer-based searching of chemical databases, molecular modeling, computer-aided molecular design of new materials, catalysts, or ligands, development of new computational methods or efficient algorithms for chemical software, and biopharmaceutical chemistry including analyses of biological activity and other issues related to drug discovery. Astute chemists, computer scientists, and information specialists look to this monthly’s insightful research studies, programming innovations, and software reviews to keep current with advances in this integral, multidisciplinary field. As a subscriber you’ll stay abreast of database search systems, use of graph theory in chemical problems, substructure search systems, pattern recognition and clustering, analysis of chemical and physical data, molecular modeling, graphics and natural language interfaces, bibliometric and citation analysis, and synthesis design and reactions databases.