Ion channels are transmembrane proteins that are widely distributed in a range of tissues and modulate the flow of ions, and hence the electrostatic potential, across the membrane.

The transition between the ‘open’ and ‘closed’ states of an ion channel is controlled by various actions, ligand-binding, voltage-sensing, temperature changes, and mechano-sensing. Ion channel drug discovery remains challenging despite the fact that several drugs targeting members of this protein family have reached the market, for example amlodipine and nateglinide. Recent progress using cryo-electron microscopy (for example, the ground-breaking work carried out by Liao et al.¹ to determine the structure of the TRPV1 ion channel) has opened the door to the further understanding and advancement of this area by supplying the drug research community with structural data on these complex systems.

Ion Channel Services at Domainex

Domainex scientists have worked on numerous ion channel programmes at all stages of preclinical research from hit identification through to candidate nomination.

Our cell biologists have established a range of assays in order to support integrated ion channel drug discovery programmes using our FLIPR platform. This allows us to use voltage-sensitive dyes to measure the effect of compounds on the ionic flux across the membrane of intact cells. In addition to our internal biology capabilities, Domainex also works closely with Metrion Biosciences to offer integrated ion channel research projects incorporating their state-of-the-art electrophysiology expertise to measure the potency, efficacy and selectivity of compounds designed and synthesised by our medicinal chemists.

Metrion Biosciences is also able to provide cardiac ion channel safety panel assessments that are CiPA compliant.

TRPA1 Antagonists

Our medicinal and computational chemists are experienced at designing and optimising compounds that exhibit a variety of binding modes, including agonists and antagonists. One example of an integrated programme is a collaboration with Metrion Biosciences to identify antagonists of the transient receptor potential cation channel A1 (TRPA1). Domainex utilised its LeadBuilder virtual screening platform in order to identify potential hit compounds, which were subsequently screened by Metrion. This resulted in the identification of small-molecule hits with micromolar potency from several different chemotypes, which were suitable for further optimization. Click here to see our poster which provides further details of this collaborative project.

If you would like to access the Domainex services in ion channel drug research to support your own programme we would be delighted to hear from you.

Reference

1. Structure of the TRPV1 Ion Channel Determined by Electron Cryo-Microscopy. Maofu Liao, Erhu Cao, David Julius and Yifan Cheng; Nature, 2013, 504, 7478.