Significance Structures of G protein-coupled receptors (GPCRs) in complex with ligands mainly provide frozen pictures with little information about the actual molecular mechanism of action of the ligand in the normally highly dynamic receptor. Through computer-based molecular dynamics simulations of a receptor for long-chain fatty acids, free fatty acid receptor 1 (FFAR1), we discover that an unoccupied, solvent-exposed pocket closes on removal of the lipid-like agonist; that is, during a major conformational change of the receptor. Importantly, a compound designed to prevent closure of this previously unrecognized, dynamic pocket was identified through structure-based virtual screening and shown to function as an allosteric agonist for the receptor. The study demonstrates that molecular dynamics simulations can be used in drug discovery to identify different modes of stabilizing specific receptor states.