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.

^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.