Table 1. Summary of properties collected in the course of this study.
The specific values for each ligand pair included in our study are available as Dataset S1. p-values values refer to the statistical significance of the difference between distributions of each property between the paired ligands that change binding mode versus those that did not change binding mode, in all cases evaluated using the one-tailed Mann Whitney U-test. AUCROC values refer to the area under the curve for the corresponding ROC plots (Figure S7). Certain properties (indicated) cannot be calculated without a crystal structure solved in complex with the larger ligand; thus, they are not immediately useful for predicting whether a small ligand will preserve its binding mode upon chemical elaboration.
| Property | Description | p-value | AUCROC | Requires crystal structure of larger ligand |
|---|---|---|---|---|
| RMAC | RMSD after minimization of the large ligand, when aligned onto the small ligand’s complex (Å) | 6×10−7 | 0.74 | |
| Pocket Volume | Volume of the pocket in the structure of the smaller ligand (Å3) | 9×10−5 | 0.68 | |
| MW | Molecular weight of the smaller ligand (Da) | 4×10−4 | 0.67 | |
| FO score | Fraction overlap of the smaller ligand with the “binding energy hot spot” from the larger ligand, defined in 24 | 5×10−4 | 0.66 | ✓ |
| Buried SASA | Solvent accessible surface area buried upon binding of the smaller ligand (Å2) | 9×10−4 | 0.65 | |
| Num heavyatoms | Number of non-hydrogen atoms in the smaller ligand | 4×10−4 | 0.64 | |
| clogP | Computed octanol-water partition coefficient | 0.02 | 0.61 | |
| pActivity | −log10 of the smaller ligand’s Kd/Ki | 0.005 | 0.61 | |
| RMSDpocket | RMSD difference of binding site residues between the two ligand-bound structures (Å) | 0.03 | 0.60 | ✓ |
| B-factor | Crystallographic B-factors of the binding site residues, relative to the rest of the (smaller ligand’s) protein structure | 0.06 | 0.57 | |
| Pocket druggability | Predicted druggability score (from PockDrug) | 0.07 | 0.58 | |
| Pocket hydrophobicity | Hydrophobicity of pocket residues | 0.08 | 0.57 | |
| θlig | Fraction of the smaller ligand’s SASA that remains exposed upon binding to the protein | 0.2 | 0.56 | |
| Intermolecular Hbonds | Number of intermolecular hydrogen bonds in the smaller ligand’s complex | 0.02 | 0.53 | |
| Fraction polar | Frequency of polar residues in the smaller ligand’s binding pocket | 0.2 | 0.53 | |
| Fraction aromatic | Frequency of aromatic residues in the smaller ligand’s binding pocket | 0.4 | 0.50 | |
| Num rotatable bonds | Number of rotatable bonds in the smaller ligand | 0.1 | 0.50 |