Fragtory: Pharmacophore-Focused Design, Synthesis, and Evaluation of an sp 3 -Enriched Fragment Library.

Autor: Bührmann M; Department of Chemistry and Chemical Biology, TU Dortmund University, Otto-Hahn-Strasse 4a, Dortmund 44227, Germany.; Drug Discovery Hub Dortmund (DDHD) am Zentrum für integrierte Wirkstoffforschung (ZIW), Dortmund 44227, Germany., Kallepu S; Department of Chemistry and Chemical Biology, TU Dortmund University, Otto-Hahn-Strasse 4a, Dortmund 44227, Germany., Warmuth JD; Department of Chemistry and Chemical Biology, TU Dortmund University, Otto-Hahn-Strasse 4a, Dortmund 44227, Germany., Wiese JN; Department of Chemistry and Chemical Biology, TU Dortmund University, Otto-Hahn-Strasse 4a, Dortmund 44227, Germany., Ehrt C; Department of Chemistry and Chemical Biology, TU Dortmund University, Otto-Hahn-Strasse 4a, Dortmund 44227, Germany., Vatheuer H; Department of Chemistry and Chemical Biology, TU Dortmund University, Otto-Hahn-Strasse 4a, Dortmund 44227, Germany., Hiller W; Department of Chemistry and Chemical Biology, TU Dortmund University, Otto-Hahn-Strasse 4a, Dortmund 44227, Germany., Seitz C; Max Planck Institute of Molecular Physiology, Compound Management and Screening Center (COMAS), Otto-Hahn-Strasse 11/15, Dortmund 44227, Germany., Levy L; Drug Discovery Hub Dortmund (DDHD) am Zentrum für integrierte Wirkstoffforschung (ZIW), Dortmund 44227, Germany.; Taros Chemicals GmbH & Co. KG, Emil-Figge-Strasse 76a, Dortmund 44227, Germany., Czodrowski P; Department of Chemistry and Chemical Biology, TU Dortmund University, Otto-Hahn-Strasse 4a, Dortmund 44227, Germany., Sievers S; Drug Discovery Hub Dortmund (DDHD) am Zentrum für integrierte Wirkstoffforschung (ZIW), Dortmund 44227, Germany.; Max Planck Institute of Molecular Physiology, Compound Management and Screening Center (COMAS), Otto-Hahn-Strasse 11/15, Dortmund 44227, Germany., Müller MP; Department of Chemistry and Chemical Biology, TU Dortmund University, Otto-Hahn-Strasse 4a, Dortmund 44227, Germany., Rauh D; Department of Chemistry and Chemical Biology, TU Dortmund University, Otto-Hahn-Strasse 4a, Dortmund 44227, Germany.; Drug Discovery Hub Dortmund (DDHD) am Zentrum für integrierte Wirkstoffforschung (ZIW), Dortmund 44227, Germany.
Jazyk: angličtina
Zdroj: Journal of medicinal chemistry [J Med Chem] 2023 May 11; Vol. 66 (9), pp. 6297-6314. Date of Electronic Publication: 2023 May 02.
DOI: 10.1021/acs.jmedchem.3c00187
Abstrakt: Fragment-based drug discovery has played an important role in medicinal chemistry and pharmaceutical research. Despite numerous demonstrated successes, the limited diversity and overrepresentation of planar, sp 2 -rich structures in commercial libraries often hamper the full potential of this approach. Hence, the thorough design of screening libraries inevitably determines the probability for meaningful hits and subsequent structural elaboration. Against this background, we present the generation of an exclusive fragment library based on iterative entry nomination by a specifically designed computational workflow: "Fragtory". Following a pharmacophore diversity-driven approach, we used Fragtory in an interdisciplinary academic setting to guide both tailored synthesis efforts and the implementation of in-house compounds to build a curated 288-member library of sp 3 -enriched fragments. Subsequent NMR screens against a model protein and hit validation by protein crystallography led to the identification of structurally novel ligands that were further characterized by isothermal titration calorimetry, demonstrating the applicability of our experimental approach.
Databáze: MEDLINE