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

• Published in: Chemical communications (Cambridge, England) Vol. 57; no. 92; pp. 1235 - 1238
• Main Authors: Matricon, Pierre, Vo, Duc Duy, Gao, Zhan-Guo, Kihlberg, Jan, Jacobson, Kenneth A, Carlsson, Jens
• Format: Journal Article
• Language: English
• Published: CAMBRIDGE Royal Soc Chemistry 19.11.2021; Royal Society of Chemistry; The Royal Society of Chemistry
• Subjects: Affinity; Binding; Bioinformatics; Bioinformatik; Chemistry; Chemistry, Multidisciplinary; drugs; evolution; Free energy; G-protein coupled receptors; Gibbs free energy; Ligands; Molecular dynamics; Optimization; Physical Sciences; Science & Technology; Selectivity; DRUG; A; IMPACT
• ISSN: 1359-7345; 1364-548X; 1364-548X
• DOI: 10.1039/d1cc03202j

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