Fig. 3: Metadynamics simulation suggests the dissociation process of KSI-6666 from S1PR1. | Nature Communications

Fig. 3: Metadynamics simulation suggests the dissociation process of KSI-6666 from S1PR1.

From: Pseudoirreversible inhibition elicits persistent efficacy of a sphingosine 1-phosphate receptor 1 antagonist

Fig. 3

a Difference between KSI-6666 enantiomers in inhibitory activities against GTP binding to S1PR1 induced by 10 nM Merck S1PR1 agonist. Data were obtained from three independent experiments. Results are expressed as the mean ± s.e.m. Magenta line, (RS)-KSI-6666; cyan line, (R)-KSI-6666; green line, (S)-KSI-6666. b Effect of (RS)-KSI-6666, (R)-KSI-6666, and (S)-KSI-6666 on leukocyte number in blood of rats. Each compound was orally administered to SD rats at 3 mg/kg. Leukocytes in the blood were counted at the indicated times. Leukocyte number was normalized as a percentage from the baseline count before the administration (n = 3 rats /group; mean ± s.e.m.). c Docking pose of (R)-KSI-6666 and crystallographic pose of W146 with S1PR1. In the merged figure, (R)-KSI-6666 and W146 are depicted in green and gray, respectively. d Ligand RMSD (root mean square deviation) values during conventional molecular dynamics (cMD) simulations of (R)-KSI-6666- and W146-bound S1PR1. The plot shows the temporal changes in the structural stability of the ligand binding over the course of the molecular dynamics simulation. e Plots of binding free-energy profiles (kcal/mol) against the distance between the center of mass of the ligand-binding residues and the ligand in metadynamics (MetaD) trajectories for (R)-KSI-6666 and W146 in the dissociation pathway from S1PR1. The results from all ten simulation runs are plotted for each compound. f Plots of ligand root mean-square deviation against simulation time in the MetaD trajectories for (R)-KSI-6666 and W146 in the dissociation pathways from S1PR1. The results from all ten runs are plotted for each compound. g Representative trajectory images showing the dissociation path of (R)-KSI-6666 from S1PR1 predicted from metadynamics simulation. Sequential snapshots (every 10 ns of two representative runs) capturing key intermediate stages in the dissociation process are exhibited. (R)-KSI-6666 undergoes dissociation from the spatial region situated between Helix I (highlighted in blue) and Helix VII (highlighted in red) within the structure of S1PR1. Source data are provided as a Source Data file.

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