Fragment-based design of selective GPCR ligands guided by free energy simulations. Issue 92 (4th November 2021)

• Record Type: Journal Article
• Authors: Matricon, Pierre; Vo, Duc Duy; Gao, Zhan-Guo; Kihlberg, Jan; Jacobson, Kenneth A.; Carlsson, Jens
• Is Part Of: Chemical communications. Volume 57:Issue 92(2021)
• Page Start: 12305
• Page End: 12308
• Publication Date: 2021-11-04
• Subjects: Chemistry -- Periodicals; 540
• DOI: 10.1039/d1cc03202j
• Languages: English
• ISSNs: 1359-7345

Abstract

Abstract : Fragment-based drug discovery relies on successful optimization of weakly binding ligands for affinity and selectivity. Abstract : 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.