Ion Channels in Drug Discovery

Although living organisms are often viewed as complex machines run by chemical reactions, there are many critical functions in living organisms that cannot be accomplished solely by chemical means. In many cases, the generation of an electrical impulse or voltage gradient is required. Ion channels, transmembrane protein assemblies that regulate the flow of ions across biological barriers, play a major role in this process. It has been demonstrated that ion channels are widely expressed and appear to be related to the development of many diseases including cancers, epilepsy, and cystic fibrosis. Based on our mature technologies in the field of protein science, Creative Biolabs has exploited the area of ion channels research such as structure-activity relationship studies, drug target screening, and novel drug design. We are glad to share our experience in ion channels studies with our global clients.

Fig.1 Representation of the basic structural
components of an ion channel. (Bagal, 2013)

Introduction of Ion Channels

Although ion channels are widely supposed to be composed of protein since have been discovered, direct crystallographic evidence of the structural details of ion channels did not become available until 1998 and won the Nobel Prize in 2003.

Ion channels are a collection of protein domains that together create a water-filled pore to allow the passage of ions through a cell membrane in response to chemical stimuli, temperature changes, or mechanical forces. These pore-forming domains vary enormously in sequence and topology but are typically composed of four or five helices that fit together to form a barrel-like structure. In order to fulfill the function of selectively filtering ions through a biological membrane, most ion channels also possess a pore-loop region called the ion or selectivity filter that regulates which ions are permitted through the pore.

Mechanism of Ion Channels

A key feature of ion channels is the mechanism through which they are activated which is referred to as a “gating mechanism”. In general, ion channels remain closed in the absence of an external stimulus. The action of a stimulating event or agent causes conformational changes in the proteins, opening the “gate” and allowing the flow of ions across a biological barrier. The ion channel gating mechanism system identifies three main groups, namely the voltage-gated channels, the extracellular ligand-gated channels, and channel proteins utilizing other gating mechanisms.

Fig.2 Mechanism of ligand-gated channels and voltage-gated channels. (Blass, 2015)

Ion Channels as Drug Targets

The human genome encodes at least 400 ion channel family members and occupies about 1.5%, representing the second-largest class of membrane proteins for drug discovery after G protein-coupled receptors. Roughly 18% of small molecule drugs listed in the ChEMBL database are targeted towards ion channels, with global sales estimated to be $12 billion. Although it is well validated that ion channels are at the core of many diseases, approved drugs are available for only a small percentage about 8% of this protein class.

Fig.3 Ion channel drugs in research and clinical pipeline as of 2016. (Hutchings, 2019)

Ion channels remain significantly under-exploited as drug targets, which provides huge potential in novel drug target developments. As a world-leading biology company, Creative Biolabs got into the ion channels targets development and gained some achievements. If you are interested in drug target development or other fields in therapeutic molecular development, please feel free to contact us.

References

1. Bagal, R. K.; et al. Ion channels as therapeutic targets: a drug discovery perspective. Journal of medicinal chemistry. 2013, 56(3), 593-624.
2. Blass, B. E. Basic principles of drug discovery and development. Elsevier. 2015.
3. Hutchings, C. J.; et al. Ion channels as therapeutic antibody targets. MAbs. 2019, 11(2), 265-296.