Sphingosine-1-phosphate receptor 1 (S1P1R), a member of the G protein-coupled receptor (GPCR) family, is an attractive protein target for the treatment of autoimmune diseases, and a diverse array of S1P1R agonists have been developed. Rational drug design based on S1P1R remains challenging due to the limited information available on the binding mode between S1P1R and its agonists. In this work, the active-like state of S1P1R was modeled via Gaussian accelerated molecular dynamics (GaMD) based on its inactive form, which was further validated by docking studies with two representative S1P1R agonists. Moreover, with the usage of the induced active-like state, the binding mode between S1P1R and its agonists was studied through molecular dynamics simulations and MM-GBSA calculations. The results of those studies indicated that four groups of binding site residues were the major contributors to the ligand and receptor interactions. In addition, this model was verified by five chemically similar compounds synthesized in-house and 1145 known S1P1R agonists collected from the BindingDB database. The elucidation of the key binding characteristics will further complete the cognition of S1P1R, which can guide the rational design of novel S1P1R agonists.

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