Table 1.

Highest-Ranking Hits Emerging from Virtual Screening of a Leadlike^a Library of ~1 Million Compounds to the Reactive^b (That Is, Transition State) Form of GR Versus the Outcome of Experimental GR Assays

Compound	Predicted Interaction Energy (kcal/mol) from docked poses	Predicted pKi from docked posesc	Experimental Resultsd
1	−21.996	10.1	Colloidal Aggregatee
2	−25.897	10.1	IC50 = 3.0 mM
3g	−13.530	9.9	Ki = 42 ± 10 μM
4	−20.511	9.5	IC50 = > 2.4 mMf
5	−12.156	9.1	Ki = 59 ± 13 μM
6h	−23.950	8.3	Ki = 1.9 mM
7h	−25.015	7.2	IC50 = 3.5 mM
8	−14.367	6.6	IC50 = 4.0 mM

^aThe Chemical Computing Group Conformational Database Version 2007, where lead-likeness is based on Oprea’s parameters;¹⁴ see Computational Procedures in the Supporting Information.

^bThe reactive form of GR, as characterized by Spies et al.⁹

^cAs determined by the London dG scoring function, implemented within the LigX utility of MOE (v2008.10);¹⁵ values above pK_i=9.0 were considered for experimental investigation.

^dAll K_i or IC₅₀ values determined by the circular dichroism assay are described in the Supporting Information, except for 1 and 4.

^eCompound 1 appeared to display noncompetitive inhibition with an apparent K_i=90 ± 7 μM but was found to inhibit GR through colloidal aggregation.

^fInhibition by 4 was measured using the coupled enzyme assay, and the actual IC₅₀ is expected to be higher due to partial inhibition of the coupled enzyme, L-glutamate dehydrogenase (see the Supporting Information for details).

^gSynthesis and derivatization of 3 are described by Fatiadi and Bou et al.¹⁶,¹⁷

^hCompounds 6 and 7 were chosen for their high interaction energies, while 8 was a readily available fragment of 2, 4, 5, and 6.