通过目录进行筛选、生长和验证:利用天然产物库中的合成中间体,通过晶体学发现天冬氨酸蛋白酶的片段

IF 2.4 4区 材料科学 Q2 CRYSTALLOGRAPHY Crystals Pub Date : 2024-08-25 DOI:10.3390/cryst14090755
Franziska U. Huschmann, Janis Mueller, Alexander Metz, Moritz Ruf, Johanna Senst, Serghei Glinca, Johannes Schiebel, Andreas Heine, Gerhard Klebe
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引用次数: 0

摘要

利用 AnalytiCon 收集的中间体直接在蛋白质晶体上进行片段筛选,这些中间体已被用于生成较大的合成天然产物类分子库。在使用天冬氨酸蛋白酶内硫胃蛋白酶进行筛选时,具有良好平衡理化特性的片段显示出令人印象深刻的高命中率。AnalytiCon 的综合文库设计有助于对发现的片段进行后续验证和扩展。由于筛选出的片段是中间体,与具有调节取代模式的较大且密切相关的类似物具有共同的核心,因此可以检索现成的后续化合物,从而开发出片段优化的设计策略。通过选择一组放大的后续化合物,可以验证在多个片段中发现的有前景的双环核心支架。由于结合模式发生了意想不到的变化,配体效率也没有显著提高,这个系列很快就被认为不合适,因此停止了研究。另外两个片段的后续化合物的结构有助于评估两个重叠片段的可能融合。提出了如何融合这两个片段的设计概念,有助于规划合适的取代模式和有前景的中心桥接元素。
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Screening, Growing, and Validation by Catalog: Using Synthetic Intermediates from Natural Product Libraries to Discover Fragments for an Aspartic Protease Through Crystallography
Fragment screening directly on protein crystals has been applied using AnalytiCon’s collection of intermediates that have been utilized to generate libraries of larger synthetic natural product-like molecules. The fragments with well-balanced physicochemical properties show an impressively high hit rate for a screen using the aspartic protease endothiapepsin. The subsequent validation and expansion of the discovered fragment hits benefits from AnalytiCon’s comprehensive library design. Since the screened fragments are intermediates that share a common core with larger and closely related analogs with modulated substitution patterns, they allow for the retrieval of off-the-shelf follow-up compounds, which enable the development of design strategies for fragment optimization. A promising bicyclic core scaffold found in several fragment hits could be validated by selecting a set of enlarged follow-up compounds. Due to unexpected changes in binding mode and no significant improvement in ligand efficiency, this series was quickly deemed unsuitable and therefore discontinued. The structures of follow-up compounds of two other fragments helped to evaluate a putative fusion of two overlapping fragment hits. A design concept on how to fuse the two fragments could be proposed and helps to plan a suitable substitution pattern and promising central bridging element.
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来源期刊
Crystals
Crystals CRYSTALLOGRAPHYMATERIALS SCIENCE, MULTIDIS-MATERIALS SCIENCE, MULTIDISCIPLINARY
CiteScore
4.20
自引率
11.10%
发文量
1527
审稿时长
16.12 days
期刊介绍: Crystals (ISSN 2073-4352) is an open access journal that covers all aspects of crystalline material research. Crystals can act as a reference, and as a publication resource, to the community. It publishes reviews, regular research articles, and short communications. Our aim is to encourage scientists to publish their experimental and theoretical results in as much detail as possible. Therefore, there is no restriction on article length. Full experimental details must be provided to enable the results to be reproduced. Crystals provides a  forum for the advancement of our understanding of the nucleation, growth, processing, and characterization of crystalline materials. Their mechanical, chemical, electronic, magnetic, and optical properties, and their diverse applications, are all considered to be of importance.
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