The next OpenADMET blind challenge focuses on predicting human Pregnane-X Receptor (hPXR) induction.
The pregnane X receptor (hPXR) is the major determinant of CYP3A gene regulation by drugs and other xenobiotics. In addition, PXR mediates induction of P450s 2B6, 2C8/9, and 3A4, as well as the drug transporters MDR1, organic anion transporting polypeptide C, bile salt export protein, and multidrug resistance-associated protein 2.
Binding site is large and hydrophobic with several important hydrogen bonding interactions. May be multiple binding conformations. Similar to CYP3A pharmacophore, many (but not all) CYP3A substrates/inhibitors are also CYP3A inducers.
The PDB structure of PNU-142721 bound to PXR highlights a number of the issues with docking studies, PDB 3R8D
PXR employs one hydrogen bond and fourteen van der Waals contacts to interact with the ligand, but allows two loops adjacent to the ligand-binding pocket to remain disordered in the structure. These observations highlight the role structural flexibility plays in PXR’s promiscuous responses to xenobiotics.
This challenge features two distinct tracks, each with its own leaderboard and structure
- Activity Prediction: Predicting the pEC50 values for a test set of 513 compounds (split into two stages).
- Structure Prediction: Predicting the bound structures of 110 ligands to PXR.
Full details of the challenge can be found here https://openadmet.ghost.io/announcing-the-next-openadmet-blind-challenge-predicting-pxr-induction/