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Hit-Optimization Using Target-Directed Dynamic Combinatorial Chemistry: Development of Inhibitors of the Anti-Infective Target 1-Deoxy-D-Xylulose-5-Phosphate Synthase

preprint
submitted on 21.07.2020 and posted on 22.07.2020 by Ravindra P. Jumde, Melissa Guardigni, Robin M. Gierse, Alaa Alhayek, Di Zhu, Zhoor Hamed, Sandra Johannsen, Walid A. M. Elgaher, Jörg Haupenthal, Anna K.H. Hirsch

Target-directed dynamic combinatorial chemistry (tdDCC) enables the identification, as well as optimization of ligands for un(der)explored targets such as the anti-infective target 1‑deoxy‑d‑xylulose-5-phosphate synthase (DXS). We report the unprecedented use of tdDCC to first identify and subsequently optimize inhibitors of the anti-infective target DXS. Using tdDCC, we were able to generate acylhydrazone-based inhibitors for DXS. The tailored tdDCC runs also provided insights into the structure–activity relationship of this novel class of DXS inhibitors. This approach holds the potential to expedite the drug discovery process and could be generally applied to a range of biological targets.

Funding

Intra-European Marie Skłodowska-Curie actions fellowship under Horizon-2020 (796089–NovInDXS, R. P. J.)

European Research Council (ERC Starting grant: 757913, A. K. H. H.)

The Netherlands Organisation for Scientific Research (LIFT grant: 731.015.414, A. K. H. H.)

The Helmholtz Association’s Initiative and Networking Fund

History

Email Address of Submitting Author

Ravindra.Jumde@helmholtz-hzi.de

Institution

Helmholtz Institute for Pharmaceutical Research Saarland

Country

Germany

ORCID For Submitting Author

0000-0002-2674-9605

Declaration of Conflict of Interest

The authors declare no competing financial interest.

Version Notes

Draft_version-1.0

Exports