Constructing an atomic-resolution model of human P2X7 receptor followed by pharmacophore modeling to identify potential inhibitors

• A reliable 3D model for P2X7 receptor is developed by using homology modelling and MD simulation.
• A pharmacophore model was constructed to discover small-molecule inhibitors of P2X7 receptor.
• Two different databases were screened by means of validated pharmacophore model.
• Docking analysis shows important residues in binding of lead compounds.

The P2X purinoceptor 7 (P2X7R) is a trimeric ATP-activated ion channel gated by extracellular ATP. P2X7R has important role in numerous diseases including pain, neurodegeneration, and inflammatory diseases such as rheumatoid arthritis and osteoarthritis. In this prospective, the discovery of small-molecule inhibitors for P2X7R as a novel therapeutic target has received considerable attention in recent years. At first, 3D structure of P2X7R was built by using homology modeling (HM) and a 50 ns molecular dynamics simulation (MDS).Ligand-based quantitative pharmacophore modeling methodology of P2X7R antagonists were developed based on training set of 49 compounds. The best four-feature pharmacophore model, includes two hydrophobic aromatic, one hydrophobic and one aromatic ring features, has the highest correlation coefficient (0.874), cost difference (368.677), low RMSD (2.876), as well as it shows a high goodness of fit and enrichment factor.Consequently, some hit compounds were introduced as final candidates by employing virtual screening and molecular docking procedure simultaneously. Among these compounds, six potential molecule were identified as potential virtual leads which, as such or upon further optimization, can be used to design novel P2X7R inhibitors.

A computational pipeline is used to construct a reliable model of P2X7 receptor and then a ligand-based quantitative pharmacophore modeling methodology was used to introduce some hit compounds.Figure optionsDownload high-quality image (202 K)Download as PowerPoint slide