Ion Channel High Throughput Screening
Metrion Biosciences and Assay.Works have formed a partnership to provide high-throughput screening capabilities for ion channel drug discovery.
Our ion channel screening capabilities enable us to provide robust, reliable data to accelerate and validate your drug discovery programmes.
An introduction to Metrion’s Ion Channel High Throughput Screening
Metrion has extensive experience of providing high quality biology services for ion channel targets.
Our team offers:
• Exceptional ion channel electrophysiology and drug discovery expertise
• A team of experienced cell biologists to create novel cell lines
• High quality, cost-effective compound screening
• Detailed characterisation of lead compounds in a range of high quality assays
• Translational services including confirmation of efficacy in stem cell and other phenotypic models
• Rapid reporting and data interpretation by experienced ion channel experts
Assay.Works offers unique and non-redundant small molecule sets which can be combined as modular high-throughput screening decks:
• 150,000 commercially available compounds with freedom to operate
• Carefully selected by experienced chemists lead-likeness and chemotype filtered
• Molecular mass and purity verified
Multi-assay High-throughput Drug Repurposing Screen:
KCNC1 Case Study
Overview
Eliana is a two-year-old from Canada with a de novo mutation (V434L) in her KCNC1 gene which encodes for the Kv3.1 channel in central nervous system neurons such as cerebellar neurons and GABAergic interneurons. The mutation manifests as a variety of neurological disorders which can include myoclonic epilepsy and ataxia due to K+ channel mutation, developmental epileptic encephalopathy (DEE), or hypotonia, depending on the specific variant. Although Eliana does not exhibit typical DEE, she suffers from hypotonia, cortical-visual impairment, vertical nystagmus, and global delays.
Eliana’s parents founded the KCNC1 Foundation, where 14 different genetic variants from 36 patients have been registered. Of these patients, 25% share the A421V variant, 12.5% share the R320H variant, a few exhibit the V432M variant, and the remaining variants are seen in 1-3 patients. Together with their partners, the foundation decided to undertake drug repurposing studies to quickly identify safe and cost-effective therapies for Eliana. The KCNC1 foundation collaborated with Metrion Biosciences, where manual and automated (Qube) patch-clamp techniques and Fluorescent Imaging Plate Reader (FLIPR) high throughput screens (HTS) against the mutant channel were performed to identify hit compounds.
Small Molecule Library
Figure 1: Physico-chemical property profile according to Lipinski’s Rule of 5 (left); Prediction of compound properties and drug-like features: Colloidal Aggregation, Permeability, Bioavailability, Solubility, PAINS.
Modular Screening Decks for Various Applications and Budgets
Figure 2: Compound sets and diversity metrics based on Bemis-Murcko clusters.
Ion Channel HTS: Metrion’s High Quality Platforms
Ion channel drug discovery is reliant on sophisticated screening platforms. Metrion employs electrophysiology platforms to deliver high quality recordings and data alongside the latest liquid handling capabilities. We also offer fluorescence-based screening capabilities suitable for HTS campaigns and follow-up profiling.
Fluorescence and luminescence
- FLIPR Penta
Automated electrophysiology
- Qube 384
- QPatch-48 (x2) and QPatch-II
Characterisation of compound activity
- Manual Patch Clamp (x8)
- Multi-Electrode Array and Impedance Recording
Liquid Handling
- Agilent Bravo
- Tecan D300e
Metrion’s Ion Channel Screening Resource library
Ion Channel Screening ResourcesPublications
- Ion Channel Drug Discovery and Modern Medicine.
- Ion Channel Discovery – Partnering to Access Specialized Expertise.
- Recent advances in electrophysiology-based screening technology and the impact upon ion channel discovery research.
- Clathrodin, hymenidin and oroidin, and their synthetic analogues as inhibitors of the voltage-gated potassium channels.
- Novel K+ Channel Targets in Atrial Fibrillation Drug Development – Where Are We?
- Human Electrophysiological and Pharmacological Properties of XEN-D0101: A Novel Atrial-Selective Kv1.5/IKur Inhibitor.
Videos and Presentations
- Designing multiple assay protocols for ligand gated ion channels using the stacked-tip feature on the Patchliner and SP384i platforms
- The benefits of targeting ion channels for pain and some of the hurdles in developing successful ion channel modulators.
Posters
- Identification of Novel Scorpion Venom Peptide Inhibitors of the Kv1.3 Ion Channel and their Potential as Drug Discovery Leads for Human T-Cell Mediated Disease.
- The development of a set of novel small molecule inhibitors of the Kv1.3 ion channel.
- A drug discovery collaboration between Japanese pharma and a UK SME CRO successfully developed novel small molecule inhibitors of the Kv1.3 channel to treat autoimmune disease.
Application notes and resources
- ASIC1a Ligand Gated Ion Channel Assay (App Note)
- Investigating the correlation between thallium flux and automated patch-clamp for ion channel activators.
- Identification of novel ion-channel binders: TRPA1 antagonist case study.
- The development of a set of novel small molecule inhibitors of the Kv1.3 ion channel.
Cardiac Safety Screening Resources- Cross-site and cross-platform variability of automated patch clamp assessments of drug effects on human cardiac currents in recombinant cells.
- A systematic strategy for estimating hERG block potency and its implications in a new cardiac safety paradigm
- The Nav 1.5 Late Current in WT and Nav 1.5 ΔKPQ Mutant Channels: An Automated Patch Clamp LQT3 Electrophysiological Assay Comparison. Safety Pharmacology Society Virtual Meeting 2020.
- NaV1.5-ΔKPQ late INa current properties and pharmacology on the SyncroPatch 384i
Neuroscience Resources- Recent advances in targeting ion channels to treat chronic pain.
- Marc Rogers (Metrion Director and Former CSO) takes part in a collaborative webinar with Nanion Technologies entitled “Validation and optimization of automated patch clamp voltage-gated Ca2+ channel assays”.
- Open access to the KCNQ channel: Retigabine and second generation M-current openers.
- Development of native and stem cell-derived electrophysiological assays for neurotoxicology screening and translational drug discovery
- Characterization of Endogenous Sodium Channels in the ND7-23 Neuroblastoma Cell Line: Implications for Use as a Heterologous Ion Channel Expression System Suitable for Automated Patch Clamp Screening.
- Optimising a difficult Nav1.8 cell line assay for automated patch clamp screening. Ion Channel Retreat, Vancouver, 2015
- Synthesis and biological evaluation of piperazine derivatives as novel isoform selective voltage-gated sodium (Nav) 1.3 channel modulators
- Action of Clathrodin and Analogues on Voltage-Gated Sodium Channels
- Novel state-dependent voltage-gated sodium channel modulators, based on marine alkaloids from Agelas sponges
- Ligand- and structure-based virtual screening for clathrodin-derived human voltage-gated sodium channel modulators
Translational Assay Resources- The role of Nav1.7 in human nociceptors: insights from human induced pluripotent stem cell-derived sensory neurons of erythromelalgia patients
- Assessment of human induced pluripotent stem cell-derived cardiomyocytes for evaluating drug-induced arrhythmias with multi-electrode array
- Development of an impedance based screening assay for cardiac safety and cardiotoxicity detection in stem cell derived cardiomyocytes
- Validation of an impedance-based phenotypic screening assay able to detect multiple mechanisms of chronic cardiotoxicity in human stem cell-derived cardiomyocytes
- Electrophysiological characterisation of Cellular Dynamics International ventricular iCell2 iPSC-derived cardiomyocytes
- Functional characterisation of human iPSC-derived atrial cardiomyocytes
Metrion’s High Throughput Screening Brochure
Let’s work together
What are your specific ion channel screening requirements?
If you have any questions, or would like to discuss your project, we will put you directly in touch with a member of our scientific team. Contact us today to discover more.