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Keywords = off-the-shelf follow-up compounds

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18 pages, 4999 KiB  
Article
Screening, Growing, and Validation by Catalog: Using Synthetic Intermediates from Natural Product Libraries to Discover Fragments for an Aspartic Protease Through Crystallography
by Franziska U. Huschmann, Janis Mueller, Alexander Metz, Moritz Ruf, Johanna Senst, Serghei Glinca, Johannes Schiebel, Andreas Heine and Gerhard Klebe
Crystals 2024, 14(9), 755; https://doi.org/10.3390/cryst14090755 - 25 Aug 2024
Viewed by 1502
Abstract
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 [...] Read more.
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. Full article
(This article belongs to the Special Issue Structural Studies in Drug Discovery and Development: From the Lead to the Pharmaceutical Form)
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