| Abstract
| - ERG2, emopamil binding protein (EBP), and sigma-1 receptor (σ1) are enzymes of sterolmetabolism and an enzyme-related protein, respectively, that share high affinity for variousstructurally diverse compounds. To discover novel high-affinity ligands, pharmacophore modelswere built with Catalyst based upon a series of 23 structurally diverse chemicals exhibiting Kivalues from 10 pM to 100 μM for all three proteins. In virtual screening experiments, weretrieved drugs that were previously reported to bind to one or several of these proteins andalso tested 11 new hits experimentally, of which three, among them raloxifene, had affinitiesfor σ1 or EBP of <60 nM. When used to search a database of 3525 biochemicals of intermediarymetabolism, a slightly modified ERG2 pharmacophore model successfully retrieved 10 substratecandidates among the top 28 hits. Our results indicate that inhibitor-based pharmacophoremodels for σ1, ERG2, and EBP can be used to screen drug and metabolite databases forchemically diverse compounds and putative endogenous ligands.
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