Fig. 4. Ligand docking simulations and substituent decomposition analysis of ONO-5430608 ligand series.

a The main scaffold and substituents. The double-ring system symmetry axis is shown as a dotted line. Rows represent different substituent’s placements around the double-ring system symmetry axis: R₁ and R₂ are on the same side (top row), R₁ is on the axis (middle row), R₁ and R₂ are on the different sides (bottom row). Ligand groups are outlined with respect to their affinities: group ‘A’ (1 nM < IC₅₀ < 100 nM, 7 ligands) in green, group ‘B’ (100 nM < IC₅₀ < 1 μM, 10 ligands) in yellow, and group ‘C’ (1 μM < IC50 < 3 μM, 6 ligands) in red. b, d Overlay of ligand binding poses (one highest-score pose per ligand) for all group ‘A’ ligands docked in the S1P₅ crystal structure (downward conformation of Y89^2.57) (b) or in a metaMD snapshot with an upward conformation of Y89^2.57 (d). c, e Clustering of docking scores for all tested ligands (5 trials per ligand) corresponding to docking runs described in b, d respectively. All ligands are grouped according to their S1P₅ affinity as described in a. The boxplots represent the median, interquartile ranges, and whiskers within 1.5 times the interquartile range.