Fragment-based design of selective GPCR ligands guided by free energy simulations.

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.

Jens Carlsson

SciLifeLab Fellow

PubMed 34734588

DOI 10.1039/d1cc03202j

Crossref 10.1039/d1cc03202j

pmc: PMC8603191
mid: NIHMS1758126

Publications 9.5.0