Fragment-based design of selective GPCR ligands guided by free energy simulations.
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ABSTRACT:
SUBMITTER: Matricon P
PROVIDER: S-EPMC8603191 | biostudies-literature | 2021 Nov
REPOSITORIES: biostudies-literature
Publications
Fragment-based design of selective GPCR ligands guided by free energy simulations.
Matricon Pierre P Vo Duc Duy DD Gao Zhan-Guo ZG Kihlberg Jan J Jacobson Kenneth A KA Carlsson Jens J
Chemical communications (Cambridge, England) 20211119 92
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. ...[more]
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