Fig. 8: Variation of FEP+ predictive accuracy across experimental structures and models of dopamine D3 receptor and GPR139.
From: AI meets physics in computational structure-based drug discovery for GPCRs
a Correlation plot of FEP+ predicted vs experimental binding affinities for the D3 receptor-eticlopride system. Each point on the plot represents one ligand from the eticlopride-related congeneric series. The gray bars represent the regions of high accuracy (error below 1 or 2 kcal/mol for dark and light gray, respectively). b Change in RB-FEP predictive accuracy for models with a range of ligand RMSD, from a previous study (non-GPCR models154). Each point corresponds to a pairwise comparison between a receptor-ligand model and its corresponding experimental structure. The change in RMSE is represented on the left y-axis (blue circles), and the change in R2 on the right y-axis (red diamonds). In both cases, the difference has been calculated so that the points that are below the x-axis correspond to an improved accuracy of the model relative to the experimental structure (i.e. ΔRMSE= RMSEModel − RMSEExperimental, while ΔR2 = R2Experimental − R2Model). c, d RMSE for RB-FEP predictions as a function of ligand RMSD (left) or receptor pocket RMSD (right), for the D3-eticlopride models (c) and the GPR139-JNJ-63353054 models (d). Each point is a complex structure. Experimental structures are shown as green dots and computational models as blue and yellow dots (yellow for the putative false positive models for GPR139 as described in the text). The shaded bars indicate the regions of high accuracy of RB-FEP predictions (RMSE below 1 kcal/mol or 1.5 kcal/mol for dark and light gray, respectively). e, f Histograms of -log10 activity for the eticlopride (e) and JNJ-63353054 (f) congeneric series used in RB-FEP calculations for D3 receptor and GPR139, respectively. g, h RB-FEP accuracy plotted against AB-FEP prediction for the D3 receptor-eticlopride models (g) and GPR139-JNJ-63353054 models (h). The color coding of the dots and bars is the same as in (c, d). The dashed line indicates the experimental ΔGbinding for eticlopride to D3 receptor (g) or JNJ-63353054 to GPR139 (h).
