Galileo: Three-dimensional searching in large combinatorial fragment spaces on the example of pharmacophores

IF 3 3区 生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY
Christian Meyenburg, Uschi Dolfus, Hans Briem, Matthias Rarey
{"title":"Galileo: Three-dimensional searching in large combinatorial fragment spaces on the example of pharmacophores","authors":"Christian Meyenburg,&nbsp;Uschi Dolfus,&nbsp;Hans Briem,&nbsp;Matthias Rarey","doi":"10.1007/s10822-022-00485-y","DOIUrl":null,"url":null,"abstract":"<div><p>Fragment spaces are an efficient way to model large chemical spaces using a handful of small fragments and a few connection rules. The development of Enamine’s REAL Space has shown that large spaces of readily available compounds may be created this way. These are several orders of magnitude larger than previous libraries. So far, searching and navigating these spaces is mostly limited to topological approaches. A way to overcome this limitation is optimization via metaheuristics which can be combined with arbitrary scoring functions. Here we present Galileo, a novel Genetic Algorithm to sample fragment spaces. We showcase Galileo in combination with a novel pharmacophore mapping approach, called Phariety, enabling 3D searches in fragment spaces. We estimate the effectiveness of the approach with a small fragment space. Furthermore, we apply Galileo to two pharmacophore searches in the REAL Space, detecting hundreds of compounds fulfilling a HSP90 and a FXIa pharmacophore.</p></div>","PeriodicalId":621,"journal":{"name":"Journal of Computer-Aided Molecular Design","volume":"37 1","pages":"1 - 16"},"PeriodicalIF":3.0000,"publicationDate":"2022-11-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s10822-022-00485-y.pdf","citationCount":"2","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Computer-Aided Molecular Design","FirstCategoryId":"99","ListUrlMain":"https://link.springer.com/article/10.1007/s10822-022-00485-y","RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q3","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
引用次数: 2

Abstract

Fragment spaces are an efficient way to model large chemical spaces using a handful of small fragments and a few connection rules. The development of Enamine’s REAL Space has shown that large spaces of readily available compounds may be created this way. These are several orders of magnitude larger than previous libraries. So far, searching and navigating these spaces is mostly limited to topological approaches. A way to overcome this limitation is optimization via metaheuristics which can be combined with arbitrary scoring functions. Here we present Galileo, a novel Genetic Algorithm to sample fragment spaces. We showcase Galileo in combination with a novel pharmacophore mapping approach, called Phariety, enabling 3D searches in fragment spaces. We estimate the effectiveness of the approach with a small fragment space. Furthermore, we apply Galileo to two pharmacophore searches in the REAL Space, detecting hundreds of compounds fulfilling a HSP90 and a FXIa pharmacophore.

Abstract Image

伽利略:以药效团为例,在大组合片段空间中的三维搜索
碎片空间是使用少量小碎片和一些连接规则来模拟大型化学空间的有效方法。Enamine 's REAL Space的开发表明,可以通过这种方式创建易于获得的化合物的大空间。这些库比以前的库要大几个数量级。到目前为止,搜索和导航这些空间主要局限于拓扑方法。克服这种限制的一种方法是通过元启发式进行优化,这可以与任意评分函数相结合。在这里,我们提出了伽利略,一个新的遗传算法来采样片段空间。我们展示了伽利略与一种新的药效团映射方法相结合,称为phariey,可以在片段空间中进行3D搜索。我们用一个小片段空间来估计该方法的有效性。此外,我们将Galileo应用于REAL空间中的两个药效团搜索,检测到数百种满足HSP90和FXIa药效团的化合物。
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
Journal of Computer-Aided Molecular Design
Journal of Computer-Aided Molecular Design 生物-计算机:跨学科应用
CiteScore
8.00
自引率
8.60%
发文量
56
审稿时长
3 months
期刊介绍: The Journal of Computer-Aided Molecular Design provides a form for disseminating information on both the theory and the application of computer-based methods in the analysis and design of molecules. The scope of the journal encompasses papers which report new and original research and applications in the following areas: - theoretical chemistry; - computational chemistry; - computer and molecular graphics; - molecular modeling; - protein engineering; - drug design; - expert systems; - general structure-property relationships; - molecular dynamics; - chemical database development and usage.
×
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