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Matricon P, Vo DD, Gao ZG, Kihlberg J, Jacobson KA, Carlsson J
Chem. Commun. (Camb.) 57 (92) 12305-12308 [2021-11-19; online 2021-11-19]
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.
PubMed 34734588
DOI 10.1039/d1cc03202j
Crossref 10.1039/d1cc03202j