Allosteric modulation of P2X receptors: a molecular and in-silico approach to understand how drug-like ligands work

FOUNTAIN_U23DTP1

P2X receptors are a family of ligand-gated ion channels activated by the neurotransmitter extracellular ATP.

Humans have 7 P2X receptor subtypes (P2X1-7) of which P2X4 has received much interest as a therapeutic target, owing to its role in neuropathic pain, vascular response to blood flow, pulmonary secretion and inflammation.

All P2X receptors have highly conserved sites for binding ATP which means these sites offer very limited opportunity for the development of subtype selective drugs. Allosteric sites offer more opportunity for sites of selective ligand binding and the development of novel drugs as they are less structurally conserved, though they are difficult to predict and require empirical determination.

Using homology modelling and in sillico approaches, we have recently identified a number of novel allosteric sites in the human P2X4 receptor that offer potential for drug development.

This project will focus on testing and refining these molecular models, to understand how drug-like molecules interact with these sites and identify new ligands for drug development.

The studentship will provide training in patch-clamp electrophysiology, mutagenesis and biochemical approaches to articulate allosteric sites in the human P2X4 receptor.

The student will also receive training in cutting-edge in silico methods including homology modelling, molecular dynamic simulations and virtual screening to determine key residues involved in ligand binding and the identification of novel ligands.

We are seeking an enthusiastic and motivated early career scientist to join our internationally recognized research team based within the Biomedical Research Centre on the University of East Anglia main campus of the Norwich Research Park.

The laboratory is generously funded by UKRI, British Heart Foundation and industrial partners.

We are a highly dynamic group and student presentation at domestic and international conferences is encouraged and supported.

References

Peter Illes, Christa E. Müller, Kenneth A. Jacobson, Thomas Grutter, Annette Nicke, Samuel J. Fountain, Charles Kennedy, Günther Schmalzing, Michael Jarvis, Stanko S. Stojilkovic, Brian F. King, Francesco Di Virgilio (2020). Update of P2X receptor properties and their pharmacology; IUPHAR review. British Journal of Pharmacology.

Richards D, Gever J, Ford AP and Fountain SJ (2019). Electrophysiological characterisation of the allosteric antagonist MK-7264 (Gefapixant) at human P2X3 and P2X2/3 receptors and functional verification in three rat models of sensitisation. British Journal of Pharmacology.

Bidula S, Nadzirin IB, Cominetti M, Hickey H, Cullum SA, Searcey M, Schmid R, Fountain SJ (2022). Structural basis of the negative allosteric modulation of 5-BDBD at Human P2X4 receptors. Molecular Pharmacology.