Selectivity by Small-Molecule Inhibitors of Protein Interactions Can Be Driven by Protein Surface Fluctuations
Fig 7
Ensembles of available pocket shapes explain ligand selectivity across the Bcl-2 family.
(A) For each inhibitor-bound pocket, the exemplar distance to the most similar pocket is indicated by color gradient, with all distances expressed as Z-scores (green are most similar, red are most dissimilar; the range of colors for each row is normalized across that row). Markings inside the cells denote experimental reports [11,51,60,67–76] for a given protein-ligand pair (Kd or Ki where available, otherwise IC50): ✔✔✔ indicates < 0.1 μM, ✔✔ indicates 0.1–1 μM, ✔ indicates binding weaker than 1 μM, and ✗ indicates that binding was not detectable/quantifiable. Cells that do not include any markings correspond to protein-ligand pairs for which binding data has not been reported. Numbering corresponds to complexes as in S1 Table. A representative subset of the complexes are included in this figure; a corresponding figure containing all complexes is available as S8 Fig. The underlying raw data are included in S5 Table (exemplar distances) and S7 Table (citations to binding data). (B) A receiver operating characteristic (ROC) plot demonstrating the performance of exemplar distances for predicting whether a given compound is active against a particular member of the Bcl-2 protein family.