IDENTIFICATION OF THE GINSENOSIDE BINDING POCKET ON THE P2X7 RECEPTOR: TOWARDS THE DEVELOPMENT OF AGENTS TO ENHANCE MICROBIAL KILLING (360G-Wellcome-207095_Z_17_Z)

The emergence of resistant prevalent bacteria as Mycobacterium tuberculosis, is boosting the development of novel strategies different to direct anti-microbial killing (antibiotics). An attractive approach is stimulating the immune system response to pathogens exploiting the existing pathways to deal with infection. This needs understanding of the mechanisms, for the development of novel modulators capable of boosting immune responses. P2X7 ion channels regulate immune responses, and activation on infected macrophages with ATP induces killing of Mycobacterium tuberculosis. Ginsenosides, known for their key role in the beneficial effects of immune system stimulation by ginseng, have been demonstrated by our collaborator, Dr Leanne Stokes, to be positive allosteric modulators of the P2X7 channel. Her research has shown the potential of enhancing P2X7 response with ginsenosides to increase microbial killing in macrophages. In this project, we will reveal the location and structural details of the binding pocket in P2X7 specific for ginsenosides of the protopanaxadiol series (Rb1, Rd, Rh2, and CK). We will use protein-ligand docking calculations on human P2X7 to predict the binding location and mode of the ligands, and molecular dynamics simulations to assess the dynamic stability of the complexes. This project will complement further NMR studies on P2X7/ginsenoside interactions.