Medicilon has a team of more than 100 chemists, and has experience in research and development cooperation with large pharmaceutical companies and biotechnology companies well-known at home and abroad. Under the leadership of experienced medicinal chemistry leaders, Medicilon provides customers with new drug development services covering a variety of targets and diseases, including from active compound discovery, target verification, lead compound optimization to the selection of preclinical drug candidates. Details.
Services: Primary and secondary screening of various ion channel drugs, discovery and optimization of lead compounds, safety evaluation, and positioning of drug targets, etc.
Detection method: automatic patch clamp or real-time fluorescence dynamic detection system
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Ion channels are one of the cornerstones of living organisms to maintain normal functions. The bioelectric signals mediated by them play a key role in all life processes such as heart beating, hormone secretion, signal transduction and cognitive memory. The mutation of ion channels at the genetic level can lead to a variety of diseases including nervous system, cardiovascular system and endocrine system diseases, so it is one of the most important drug targets and one of the indicators of drug safety evaluation. The functional detection of ion channels relies on the measurement of tiny currents mediated by them. Due to the limitation of technical means, the low screening flux of compounds has become the bottleneck and key step of drug discovery for ion channels.
The commonly used screening models are at the molecular level and the cellular level. The interaction between the drug and the molecular target is observed, and the basic mechanism of action of the drug can be directly understood.
Molecular-level drug screening model: receptor screening model; enzyme screening model; ion channel screening model
Ion channel screening model:
(1) High-throughput screening of shellfish toxins, the target of which is the saxitoxin binding site on the Na+ channel, and a competitive binding test with radioligands was conducted to examine the tested samples.
(2) High-throughput screening of small molecules that interfere with the interaction between the β3 subunit of the N-type calcium channel and the α1β subunit using yeast two-hybrid methods to find new calcium channel antagonists.
Main functions and research methods of ion channels
The main functions of the ion channel are:
(1) Increase the intracellular calcium concentration, thereby triggering a series of physiological effects such as muscle contraction, cell excitement, gland secretion, Ca2+-dependent ion channel opening and closing, protein kinase activation and gene expression regulation;
(2) In excitatory cells such as nerves and muscles, Na+ and Ca2+ channels mainly regulate depolarization, and K+ mainly regulates repolarization and maintains resting potential, thereby determining the excitability, refractoryness and conductivity of cells;
(3) Regulate vasomotor smooth muscle contraction and contraction activities, including K+, Ca2+, Cl- channels and some non-selective cation channels;
(4) Participate in synaptic transmission, including K+, Na+, Ca2+, Cl- channels and some non-selective cation channels;
(5) Maintain the normal volume of cells. In the hypertonic environment, the activation of ion channels and transport systems causes Na+, Cl-, organic solutions and water to enter the cells to regulate the increase in cell volume; in the hypotonic environment, Na+, Cl- , Organic solution and water flow out of the cell to regulate cell volume reduction.
The most direct way to study the function of ion channels is to use patch clamp technology to directly measure the current through the ion channel or to measure changes in cell membrane potential. Patch clamp technology is to use a glass micropipette electrode to complete the monitoring or clamping of the membrane or whole cell potential. And the recording of membrane currents, analyze the molecular activities of individual or groups of channels, and discuss the characteristics of ion channels by observing the changes of membrane currents. Molecular biology technology provides powerful tools for molecular structure analysis, gene cloning, and functional expression studies of ion channels. For the gene structure encoding the ion channel subunit, gene location cloning can be used to determine its location on the chromosome, reverse transcription-polymerase chain reaction, Northern hybridization, etc. to clarify its distribution in organ tissues, and Western hybridization to detect gene expression products Fluorescent probe calcium image analysis technology provides an effective means for detecting intracellular free calcium ion concentration. Commonly used fluorescent probes are Fura-2/AM, Indo-1/AM, Fluo-3/AM, Calcium Green, etc. Commonly used detection instruments include dual-wavelength microfluorescence photometer, laser scanning confocal microscope, etc. At present, foreign companies such as Olympus, Zeiss, Spex, etc. have produced micro-fluorescence devices for measuring intracellular free calcium ions, and domestically developed living cells Calcium ion fluorescence microscopic detection system has also been introduced. Combining ion concentration image recording and patch-clamp recording, simultaneous photoelectric detection is used to study ion channels from the aspects of ion concentration, image changes, and electrical signal changes generated by ions, and more information about ion channel functions will be obtained.