Discovery of high-affinity ligands of sigma1 receptor, ERG2, and emopamil binding protein by pharmacophore modeling and virtual screening.
ERG2, emopamil binding protein (EBP), and sigma-1 receptor (sigma(1)) are enzymes of sterol metabolism and an enzyme-related protein, respectively, that share high affinity for various structurally diverse compounds. To discover novel high-affinity ligands, pharmacophore models were built with Catalyst based upon a series of 23 structurally diverse chemicals exhibiting K(i) values from 10 pM to 100 microM for all three proteins. In virtual screening experiments, we retrieved drugs that were previously reported to bind to one or several of these proteins and also tested 11 new hits experimentally, of which three, among them raloxifene, had affinities for sigma(1) or EBP of <60 nM. When used to search a database of 3525 biochemicals of intermediary metabolism, a slightly modified ERG2 pharmacophore model successfully retrieved 10 substrate candidates among the top 28 hits. Our results indicate that inhibitor-based pharmacophore models for sigma(1), ERG2, and EBP can be used to screen drug and metabolite databases for chemically diverse compounds and putative endogenous ligands.
Laggner
Christian
C
Institute of Pharmacy, Department of Pharmaceutical Chemistry, and Center for Molecular Biosciences (CMBI), University of Innsbruck, Innrain 52, A-6020 Innsbruck, Austria.
Schieferer
Claudia
C
Fiechtner
Birgit
B
Poles
Gloria
G
Hoffmann
Rémy D
RD
Glossmann
Hartmut
H
Langer
Thierry
T
Moebius
Fabian F
FF
D000818:Animals; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism; D016208:Databases, Factual; D006168:Guinea Pigs; D006801:Humans; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D007536:Isomerism; D008024:Ligands; D008958:Models, Molecular; D021281:Quantitative Structure-Activity Relationship; D011869:Radioligand Assay; D017480:Receptors, sigma / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000378:metabolism; D013251:Steroid Isomerases / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism; D000097605:Sigma-1 Receptor
D002352:Carrier Proteins; D008024:Ligands; D017480:Receptors, sigma; D013251:Steroid Isomerases; D000097605:Sigma-1 Receptor; C090445:EBP protein, human