In silico screening of GMQ-like compounds reveals guanabenz and sephin1 as new allosteric modulators of acid-sensing ion channel 3.

Publication date: Feb 03, 2020

Acid-sensing ion channels (ASICs) are voltage-independent cation channels that detect decreases in extracellular pH. Dysregulation of ASICs underpins a number of pathologies. Of particular interest is ASIC3, which is recognised as a key sensor of acid-induced pain and is important in the establishment of pain arising from inflammatory conditions, such as rheumatoid arthritis. Thus, the identification of new ASIC3 modulators and the mechanistic understanding of how these compounds modulate ASIC3 could be important for the development of new strategies to counteract the detrimental effects of dysregulated ASIC3 activity in inflammation. Here, we report the identification of novel ASIC3 modulators based on the ASIC3 agonist, 2-guanidine-4-methylquinazoline (GMQ). Through a GMQ-guided in silico screening of Food and Drug administration (FDA)-approved drugs, 5 compounds were selected and tested for their modulation of rat ASIC3 (rASIC3) using whole-cell patch-clamp electrophysiology. Of the chosen drugs, guanabenz (GBZ), an ?-adrenoceptor agonist, produced similar effects to GMQ on rASIC3, activating the channel at physiological pH (pH 7.4) and potentiating its response to mild acidic (pH 7) stimuli. Sephin1, a GBZ derivative that lacks ?-adrenoceptor activity, has been proposed to act as a selective inhibitor of a regulatory subunit of the stress-induced protein phosphatase 1 (PPP1R15A) with promising therapeutic potential for the treatment of multiple sclerosis. However, we found that like GBZ, sephin1 activates rASIC3 at pH 7.4 and potentiates its response to acidic stimulation (pH 7), i.e. sephin1 is a novel modulator of rASIC3. Furthermore, docking experiments showed that, like GMQ, GBZ and sephin1 likely interact with the nonproton ligand sensor domain of rASIC3. Overall, these data demonstrate the utility of computational analysis for identifying novel ASIC3 modulators, which can be validated with electrophysiological analysis and may lead to the development of better compounds for targeting ASIC3 in the treatment of inflammatory conditions.

Callejo, G., Pattison, L.A., Greenhalgh, J.C., Chakrabarti, S., Andreopoulou, E., Hockley, J.R.F., Smith, E.S.J., and Rahman, T. In silico screening of GMQ-like compounds reveals guanabenz and sephin1 as new allosteric modulators of acid-sensing ion channel 3. 20160. 2020 Biochem Pharmacol.

Concepts Keywords
Acid
Agonist
Allosteric
ASICs
Cation
Derivative
Electrophysiological
Extracellular
FDA
Guanidine
Inflammation
Inhibitor
Interact
Ion Channel
Ion Channels
Lead Compounds
Ligand
Modulation
Multiple Sclerosis
Pain
Patch Clamp Electrophysiology
Pathologies
PH
Phosphatase
Rheumatoid Arthritis
Sensor
Stress
Voltage

Semantics

Type Source Name
drug DRUGBANK Guanabenz
disease MESH rheumatoid arthritis
pathway KEGG Rheumatoid arthritis
disease MESH development
disease MESH inflammation
drug DRUGBANK Guanidine
disease MESH multiple sclerosis
drug DRUGBANK Tropicamide

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