Docking of competitive inhibitors to the P2X7 receptor family reveals key differences responsible for changes in response between rat and human

Bioorg Med Chem Lett. 2015 Aug 15;25(16):3164-7. doi: 10.1016/j.bmcl.2015.06.001. Epub 2015 Jun 6.


The P2X7 receptor is a calcium permeable cationic channel activated by extracellular ATP, playing a role in chronic pain, osteoporosis and arthritis. A number of potential lead compounds are inactive against the rat isoform, despite good activity against the human homologue, making animal model studies problematic. Here we have produced P2X7 models and docked three structurally distinct inhibitors using in silico approaches and show they have a similar mode of binding in which Phe95 plays a key role by forming pi-stacking interactions. Importantly this residue is replaced by Leu in the rat P2X7 receptor resulting in a significantly reduced binding affinity. This work provides new insights into binding of P2X7 inhibitors and shows the structural difference in human and rat P2X7 receptors which results in a difference in affinity. Such information is useful both for the rational design of inhibitors based on these scaffolds and also the way in which these compounds are tested in animal models.

Keywords: AZ11645373; Adenosine triphosphate; KN62; P2X7 receptor; SB203580.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphate / metabolism
  • Amino Acid Sequence
  • Animals
  • Binding Sites
  • Humans
  • Molecular Docking Simulation
  • Molecular Sequence Data
  • Protein Structure, Tertiary
  • Purinergic P2X Receptor Antagonists / chemistry*
  • Purinergic P2X Receptor Antagonists / metabolism
  • Rats
  • Receptors, Purinergic P2X7 / chemistry*
  • Receptors, Purinergic P2X7 / metabolism
  • Sequence Alignment


  • Purinergic P2X Receptor Antagonists
  • Receptors, Purinergic P2X7
  • Adenosine Triphosphate