Predicted and observed results using the PXR antagonist pharmacophores
GOLD docking scores and biological data after using the antagonist lead SPB03255 for substructure searching with ChemSpider and eMolecules. Docking scores in bold were the highest in the molecules tested in vitro. All molecule structures are shown in Figure 3 and Supplemental Figure 2.
| Molecule | Catalyst Shape Fit | Catalyst Hypo Fit Only | GOLD Score (AF-2 site) | Agonist Mode PXR + DMSO EC50a | Antagonist Mode PXR + RIF IC50a | |
|---|---|---|---|---|---|---|
| Rigid | Flexible | |||||
| μM | ||||||
| SPB03256 | 0.71 | 1.62 | 2.11 | 40.80 | >50 | 6.21 |
| SPB03254 | 1.76 | 1.49 | 1.76 | 43.24 | 5.23 | >50 |
| SPB06061 | — | — | 0.62 | 37.54 | >50 | 5.22 |
| SPB03259 | — | — | 0.59 | 36.80 | >50 | >50 |
| SPB03211 | 0.7 | 1.43 | 1.81 | 36.76 | 13.59 | >50 |
| SPB03213 | — | — | 1.7 | 36.65 | 1.71 | >50 |
| SPB03214 | 1.68 | 2.89 | 1.76 | 36.22 | >50 | >50 |
| SPB03215 | — | 1.37 | 1.62 | 33.64 | >50 | >50 |
| SPB03650 | 1.62 | 3.01 | 1.93 | 40.84 | N.T. | N.T. |
| SPB03651 | — | — | — | 35.81 | >50 | >50 |
| SPB03212 | — | — | — | 33.09 | N.T. | N.T. |
| SPB03663 | — | — | — | 37.55 | 16.83 | >50 |
| Pubchem- 3169346 | — | 2.26 | 0.72 | 39.81 | N.T. | N.T. |
| SPB06257 | — | 2.66 | 2.05 | 47.26 | >50 | 16.42 |
| SPB02372 | — | — | 1.44 | 42.16 | >50 | 5.82 |
| SPB06166 | — | — | — | 38.52 | N.T. | N.T. |
| SPB06259 | 1.1 | 2.72 | 1.95 | 44.88 | N.T. | N.T. |
| Leflunomide | — | — | — | 31.00 | >50 | 6.80 |
—, no fit; N.T., not tested.
↵ a Data represents single runs in duplicate.