부산대학교 도서관

Sphingosine 1-phosphate receptor-1 (S1P1), a G protein-coupled receptor, is required for the egress of lymphocytes from lymphoid organs into blood. Blocking S1P1 signaling is a promising therapeutic approach to inflammatory diseases, and the understanding of the structural basis for enhancing inhibitory activity is critical to find potent S1P1 antagonists. We discovered a novel competitive antagonist, KSI-6666, that persistently suppresses S1P1 signaling in vivo and effectively inhibit the pathogenesis in mouse colitis models. In silico studies of molecular docking and molecular dynamics suggested that the dissociation of KSI-6666 from S1P1 is obstructed by the interaction of its bulky substituent with a methionine residue in the ligand-binding pocket of S1P1. In vitro analysis revealed a pseudo-irreversible inhibition of S1P1 signaling by KSI-6666 and the structural components that hindered its dissociation from receptors, corresponding to the predicted outcomes by molecular dynamics simulation. Moreover, in vivo studies suggested that the pseudo-irreversible inhibition contributes to the persistent effect of KSI-6666. These findings would help the rationale design of potent S1P1 antagonists for the treatment of inflammatory disorders.