Journal
CHEMICAL COMMUNICATIONS
Volume 57, Issue 92, Pages 12305-12308Publisher
ROYAL SOC CHEMISTRY
DOI: 10.1039/d1cc03202j
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Funding
- European Research Council (ERC) under the European Union's Horizon 2020 research and innovation programme [715052]
- Swedish Research Council [2017-4676]
- Swedish strategic research programme eSSENCE
- National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Intramural Research Program [ZIADK31117]
- European Research Council (ERC) [715052] Funding Source: European Research Council (ERC)
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Fragment-based drug discovery relies on optimizing weakly binding ligands for affinity and selectivity, with strategies for structure-based evolution of fragments binding to a G protein-coupled receptor resulting in nanomolar ligands with significantly improved binding affinity and subtype selectivity.
Fragment-based drug discovery relies on successful optimization of weakly binding ligands for affinity and selectivity. Herein, we explored strategies for structure-based evolution of fragments binding to a G protein-coupled receptor. Molecular dynamics simulations combined with rigorous free energy calculations guided synthesis of nanomolar ligands with up to >1000-fold improvements of binding affinity and close to 40-fold subtype selectivity.
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