Fragment-based design of selective GPCR ligands guided by free energy simulations
2021
Matricon, Pierre | Vo, Duc Duy | Gao, Zhan-Guo | Kihlberg, Jan | Jacobson, Kenneth A. | Carlsson, Jens
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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