Gisbert Schneider and co-workers, Goethe-University, Frankfurt, Germany, report on target profile prediction to identify cross-activities of peroxisome proliferator-activated receptor (PPAR) and farnesoid X receptor (FXR).
PPARs were identified in the 1990s and have become most prominent targets for treatment of metabolic disorders like dyslipidemia and type 2 diabetes mellitus.
It has now been demonstrated that pharmacophore-based similarity searching may be used to predict the target profile of related bioactive compounds.
For one target, FXR, the correctness of the prediction was experimentally confirmed in a cell-based functional assay.
Figure 1. Pseudoreceptor model of compound 1 (gray) aligned with potent and subtype-selective opioid receptor agonists 3 (: IC50 = 0.87 nM; orange) and 4 (: IC50 = 0.7 nM; magenta). Potential receptor interaction sites are shown as colored spheres (green: aromatic, blue: hydrogen-bond donor). For each compound, one CORINA conformation was generated and a PRPS pseudoreceptor model computed. Only mutual pseudoreceptor sites are shown. Due to the closer resemblance of 1 and 4, it is suggested that 1 might preferably interact with opioid receptor. (C) WILEY-VCH
- Target Profile Prediction: Cross-Activation of Peroxisome Proliferator-Activated Receptor (PPAR) and Farnesoid X Receptor (FXR)
R. Steri, P. Schneider, A. Klenner, M. Rupp, J. M. Kriegl, M. Schubert-Zsilavecz, G. Schneider,
Mol. Inf. 2010, 29, 287–292.