Ion Channel Drug Discovery: Challenges And Future Directions

Wickenden, Alan D.; Priest, Birgit T.; Erdemli, Gül

doi:10.4155/fmc.12.4

Cited by 47 publications

(47 citation statements)

References 117 publications

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“…Under these conditions a large proportion of ion channels may need to be inhibited to result in a change in membrane potential resulting in large right-shifts in apparent potency potentially leading to high false-negative rates. (2) Related to point (1), the target of interest must control the membrane potential in the assay and thus target expression level may have a greater effect on membrane potential-based assays compared to ion flux assays. (3) Because voltagesensitive dyes can be modulated by not only the target of interest, but any event that changes membrane potential, false positive rates can also be very high.…”

mentioning

confidence: 99%

Development and Validation of a Thallium Flux-Based Functional Assay for the Sodium Channel NaV1.7 and Its Utility for Lead Discovery and Compound Profiling

Du¹,

Days²,

Romaine³

et al. 2015

ACS Chem. Neurosci.

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Ion channels are critical for life, and they are targets of numerous drugs. The sequencing of the human genome has revealed the existence of hundreds of different ion channel subunits capable of forming thousands of ion channels. In the face of this diversity, we only have a few selective small-molecule tools to aid in our understanding of the role specific ion channels in physiology which may in turn help illuminate their therapeutic potential. Although the advent of automated electrophysiology has increased the rate at which we can screen for and characterize ion channel modulators, the technique's high per-measurement cost and moderate throughput compared to other high-throughput screening approaches limit its utility for large-scale high-throughput screening. Therefore, lower cost, more rapid techniques are needed. While ion channel types capable of fluxing calcium are well-served by low cost, very high-throughput fluorescence-based assays, other channel types such as sodium channels remain underserved by present functional assay techniques. In order to address this shortcoming, we have developed a thallium flux-based assay for sodium channels using the NaV1.7 channel as a model target. We show that the assay is able to rapidly and cost-effectively identify NaV1.7 inhibitors thus providing a new method useful for the discovery and profiling of sodium channel modulators.

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confidence: 99%

Development and Validation of a Thallium Flux-Based Functional Assay for the Sodium Channel NaV1.7 and Its Utility for Lead Discovery and Compound Profiling

Du¹,

Days²,

Romaine³

et al. 2015

ACS Chem. Neurosci.

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“…9 The physiological importance of the voltage gated sodium channel is associated with numerous pathologies namely cardiovascular, neuronal, neuromuscular, musculoskeletal, metabolic, and respiratory systems 10,11 due to the inherited ion channel diseases due to mutations. 12,13 Discovery of drug to cure these diseases are difficult owing to the fact that thorough molecular approaches are ineffective and most ion channel drugs are discovered using lab cultured tissues and animal based pharmacological methods 14,15,16 which cannot be tested on human beforehand. The complete understanding of the mechanism of blocking of drugs and how the intrinsic properties of channel gating affect drug access, binding affinity and unblocking are still not clearly understood.…”

Section: Introductionmentioning

confidence: 99%

Probing kinetic drug binding mechanism in voltage-gated sodium ion channel: open state versus inactive state blockers

Pal

Gangopadhyay

2015

Channels

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The kinetics and nonequilibrium thermodynamics of open state and inactive state drug binding mechanisms have been studied here using different voltage protocols in sodium ion channel. We have found that for constant voltage protocol, open state block is more efficient in blocking ionic current than inactive state block. Kinetic effect comes through peak current for mexiletine as an open state blocker and in the tail part for lidocaine as an inactive state blocker. Although the inactivation of sodium channel is a free energy driven process, however, the two different kinds of drug affect the inactivation process in a different way as seen from thermodynamic analysis. In presence of open state drug block, the process initially for a long time remains entropy driven and then becomes free energy driven. However in presence of inactive state block, the process remains entirely entropy driven until the equilibrium is attained. For oscillating voltage protocol, the inactive state blocking is more efficient in damping the oscillation of ionic current. From the pulse train analysis it is found that inactive state blocking is less effective in restoring normal repolarisation and blocks peak ionic current. Pulse train protocol also shows that all the inactive states behave differently as one inactive state responds instantly to the test pulse in an opposite manner from the other two states.

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“…They also include some of the most widely prescribed drugs, such as benzodiazepines, calcium channel blockers, and sulfonylurea antidiabetic agents. As ion channel families have been identified over the past 30 years and their genes cloned (Alexander et al, 2011), there has been a major effort to develop small-molecule agonists and antagonists that are specific, selective, and safe (Wickenden et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

P2X Receptors as Drug Targets

2012

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The study of P2X receptors has long been handicapped by a poverty of small-molecule tools that serve as selective agonists and antagonists. There has been progress, particularly in the past 10 years, as cell-based high-throughput screening methods were applied, together with large chemical libraries. This has delivered some drug-like molecules in several chemical classes that selectively target P2X1, P2X3, or P2X7 receptors. Some of these are, or have been, in clinical trials for rheumatoid arthritis, pain, and cough. Current preclinical research programs are studying P2X receptor involvement in pain, inflammation, osteoporosis, multiple sclerosis, spinal cord injury, and bladder dysfunction. The determination of the atomic structure of P2X receptors in closed and open (ATP-bound) states by X-ray crystallography is now allowing new approaches by molecular modeling. This is supported by a large body of previous work using mutagenesis and functional expression, and is now being supplemented by molecular dynamic simulations and in silico ligand docking. These approaches should lead to P2X receptors soon taking their place alongside other ion channel proteins as therapeutically important drug targets.

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Ion Channel Drug Discovery: Challenges And Future Directions

Cited by 47 publications

References 117 publications

Development and Validation of a Thallium Flux-Based Functional Assay for the Sodium Channel NaV1.7 and Its Utility for Lead Discovery and Compound Profiling

Development and Validation of a Thallium Flux-Based Functional Assay for the Sodium Channel NaV1.7 and Its Utility for Lead Discovery and Compound Profiling

Probing kinetic drug binding mechanism in voltage-gated sodium ion channel: open state versus inactive state blockers

P2X Receptors as Drug Targets

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