Targeting Ion Channels for Drug Discovery: Emerging Challenges for High Throughput Screening Technologies

Ligand and voltage-gated ion channels are highly regulated protein molecules that cross the cell membrane allowing ion flow from one side of the membrane to the other. They are ubiquitously expressed in human tissues and consist of one of the largest and best understood functional groups of proteins, with more than 400 members spanning nearly 1% of the human genome. They are involved in a variety of fundamental physiological processes, and their malfunction causes numerous diseases. In terms of the challenges faced in the effort to discover specific drugs in ancient and emerging diseases, ion channels are the third-largest class of target proteins after G-protein-coupled receptors (GPCRs) and kinases. 15% of small molecule drug targets have been reported to be voltage- or ligand-gated ion channels, resulting in approximately 150 new drug candidates in preclinical and clinical studies. Of the ion channel targeting drugs found on the market, these were identified more than a decade ago, and many of the current studies are at various stages of scientific approval. Overcoming these challenges has led the field of ion channel drug discovery to transform over the past 15 years through major advancements in genetic target detection, validation, structure-based drug design, and drug modeling of cell-based diseases.

Although ion channels are often considered difficult targets for drug discovery, significant advances have been made in understanding the pharmacology and structure of ion channels. Therefore, in recent decades, rapid progress in the development of functional assays and instrumentation has enabled high throughput detection technologies (HTS) for ion channels. They represent an important class of drug discovery targets. The development of an in vitro drug profile for targetable ion channels would be a major goal. This collection brings the most current HTS technologies for different classes of ion channels and their applications.

We will consider review articles and original research papers that report novel findings and cutting-edge studies in either of the next two sections. The first section describes the type of high throughput screening (HTS) used in the study (section 1), in which the author can select from a variety of types of approaches (subsections 1.1 to 1.7). The next section (section 2) determines the type of ion channel under study, where the author will choose the section to which it belongs (subsections 2.1 to 2.13).

1. HTS technologies:
1.1. Automated electrophysiological assays
1.2. Flux-based assays
1.3. Voltage-sensitive dye assays
1.4. Ion-specific fluorescent probes
1.5. Optogenetics
1.6. Label-free plate-based assays
1.7. Others
2. Ion channel types:
2.1. Voltage-gated potassium channels
2.2. Voltage-gated calcium channels
2.3. Voltage-gated sodium channels
2.4. K2P 2 pore channels
2.5. Glutamate receptors
2.6. GABAA receptors
2.7. Nicotinic acetylcholine receptors
2.8. Glycine receptors
2.9. Cyclic nucleotide-gated (HCN) channels
2.10. Transient receptor potential channels
2.11. Epithelial airway channels
2.12. Organellar ion channels
2.13. Transporters and others

The Topic Editors declare no competing interests with regard to the Research Topic subject