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Bottlenecks and potential improvements

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Posted: 28 September 2006 | | No comments yet

Ion channels are membrane proteins that regulate the entrance and departure of specific ions from cells, thus influencing the physiology of all cells. These ion flows also underlie electrical impulses required for sensory and motor functions of the brain, control of contraction of heart, skeletal, smooth and vascular muscle, as well as nutrient uptake, hormone secretion, cell replication and foetal development.

Ion channels are membrane proteins that regulate the entrance and departure of specific ions from cells, thus influencing the physiology of all cells. These ion flows also underlie electrical impulses required for sensory and motor functions of the brain, control of contraction of heart, skeletal, smooth and vascular muscle, as well as nutrient uptake, hormone secretion, cell replication and foetal development.

Ion channels are membrane proteins that regulate the entrance and departure of specific ions from cells, thus influencing the physiology of all cells. These ion flows also underlie electrical impulses required for sensory and motor functions of the brain, control of contraction of heart, skeletal, smooth and vascular muscle, as well as nutrient uptake, hormone secretion, cell replication and foetal development.

Good prospects for the future

So, it seems unlikely that high throughput electrophysiology will impact primary screening of ion channel targets in the short term, due to costs (consumables, instrumentation, maintenance) vs. budget restraints (out of reach for most academia), consequently costs per data point, and lack of desired instruments (e.g. cheaper patch plates of appropriately high throughput). Therewith the potential of the first-generation units to significantly shorten drug development times seems rather limited. Implementation of APC systems into safety assessment is also not likely on a short term, since this is a GLP-constrained context and by requirement the data generated by such machines must be widely accepted before change is considered, from validated assays4 (but see 7,8). APC systems will be expected to impact stages after primary screening, and the screening of smaller, biased high quality ion channel libraries. For novel routes in combinatorial chemistry directed at ion channel targets, it is of importance that APC systems would be integrated at an early stage of the drug discovery process, after primary screening of full diversity libraries (higher throughput). Doubts as to the quality of APC-generated data as compared to the manual methods can then be overcome by manual patch clamp follow up experiments, and other techniques, at a later stage (but obviously before committing significant combinatorial chemistry and resources to the ‘hit’) to verify APC data. With appropriate data quality, the use of HT electrophysiology will circumvent the disadvantage of manual clamping that the manual method usually takes place too late in the drug discovery process to have much impact on the design of novel and selective compounds1. And this was a major bottleneck in ion channel drug discovery: the inability to find molecularly different compounds to shape novel combinatorial chemistry pathways. But strategically, it is not only about numbers (albeit a key performance indicator), yet also about being able to predict which compounds have a good likelihood to survive the pipeline into the market9.

On the whole, prospects for HT electrophysiology are good: the APC market is predicted to grow with an estimated sales of more than 200 APC units globally in 2006, technological innovations relevant for APC are taking place10,11, and improved next-generation machines will surely impact turnover of HT electrophysiology machines and data quality5. Thus, novel areas of ion channel functionality research are likely within reach, hoping that the new and more rational than random approach will provide a palette of novel, selective and strong ion channel pharmacophores.

References

1. Treherne JM. Exploiting high-throughput ion channel screening technologies in integrated drug discovery. Current Pharmaceutical Design 12 (4): 397-406, 2006.
2. Jurkat-Rott K, Lehmann-Horn F. The patch clamp technique in ion channel research. Current Pharmaceutical Biotechnology 5 (4): 387-395, 2004.
3. Wood C, Williams C, Waldron GJ. Patch clamping by numbers. Drug Discovery Today 9 (10): 434-441, 2004.
4. Comley J. Automated patch clamping. Drug Discovery World Winter 2005/6: 62-79, 2005.
5. Comley J. Patchers vs. screeners. Drug Discovery World Fall 2003: 47-57, 2003.
6. Capelli AM, Feriani A et al. Generation of a focused set of GSK compounds biased towards ligand-gated ion-channel ligands. Journal of Chemical Information and Modeling 46 (2): 659-664, 2006.
7. Guthrie H, Livingston FS et al. A place for high-throughput electrophysiology in cardiac safety: screening hERG cell lines and novel compounds with the Ion Works HTTM system. Journal of Biomolecular Screening 10 (8): 832-840, 2005.
8. Sorota S, Zhang XS et al. Characterization of a hERG screen using the IonWorks HT: comparison to a hERG rubidium efflux screen. ASSAY and Drug Development Technologies 3 (1): 47-57, 2005.
9. Federsel HJ. The integration of process R&D in drug discovery – challenges and opportunities. Combinatorial Chemistry and High Throughput Screening 9 (2): 79-86, 2006.
10. Bugianesi RM, Augustine PR et al. A cell-sparing electric field stimulation technique for high-throughput screening of voltage-gated ion channels. ASSAY and Drug Development Technologies 4 (1): 21-35, 2006.
11. Ionescu-Zanetti C, Shaw RM et al. Mammalian electrophysiology on a microfluidic platform. Proceedings of the National Academy of Sciences of the U.S.A. 102 (26): 9112-9117, 2005.