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

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.

Automated summary

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.