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Discovery of novel TASK-3 channel blockers using a pharmacophore-based virtual screening

dc.contributor.authorRamírez D.
dc.contributor.authorConcha G.
dc.contributor.authorArévalo B.
dc.contributor.authorPrent-Peñaloza L.
dc.contributor.authorZúñiga L.
dc.contributor.authorKiper A.K.
dc.contributor.authorRinné S.
dc.contributor.authorReyes-Parada M.
dc.contributor.authorDecher N.
dc.contributor.authorGonzález W.
dc.contributor.authorCaballero J.
dc.date.accessioned2020-09-02T22:26:32Z
dc.date.available2020-09-02T22:26:32Z
dc.date.issued2019
dc.identifier10.3390/ijms20164014
dc.identifier.citation20, 16, -
dc.identifier.issn16616596
dc.identifier.urihttps://hdl.handle.net/20.500.12728/5950
dc.descriptionTASK-3 is a two-pore domain potassium (K2P) channel highly expressed in the hippocampus, cerebellum, and cortex. TASK-3 has been identified as an oncogenic potassium channel and it is overexpressed in different cancer types. For this reason, the development of new TASK-3 blockers could influence the pharmacological treatment of cancer and several neurological conditions. In the present work, we searched for novel TASK-3 blockers by using a virtual screening protocol that includes pharmacophore modeling, molecular docking, and free energy calculations. With this protocol, 19 potential TASK-3 blockers were identified. These molecules were tested in TASK-3 using patch clamp, and one blocker (DR16) was identified with an IC50 = 56.8 ± 3.9 µM. Using DR16 as a scaffold, we designed DR16.1, a novel TASK-3 inhibitor, with an IC50 = 14.2 ± 3.4 µM. Our finding takes on greater relevance considering that not many inhibitory TASK-3 modulators have been reported in the scientific literature until today. These two novel TASK-3 channel inhibitors (DR16 and DR16.1) are the first compounds found using a pharmacophore-based virtual screening and rational drug design protocol. © 2019 by the authors. Licensee MDPI, Basel, Switzerland.
dc.language.isoen
dc.publisherMDPI AG
dc.subjectDrug design
dc.subjectLead optimization
dc.subjectPharmacophore-based virtual screening
dc.subjectTASK channels blockers
dc.subjectTASK-3 channel
dc.subjectpotassium channel blocking agent
dc.subjectKCNK9 protein, human
dc.subjectpotassium channel blocking agent
dc.subjecttandem pore domain potassium channel
dc.subjectArticle
dc.subjectbinding site
dc.subjectcarbon nuclear magnetic resonance
dc.subjectcontrolled study
dc.subjectcrystal structure
dc.subjectFourier transform infrared spectroscopy
dc.subjecthigh throughput screening
dc.subjecthuman
dc.subjecthuman cell
dc.subjecthydrogen bond
dc.subjectmass spectrometry
dc.subjectmolecular docking
dc.subjectmolecular dynamics
dc.subjectpatch clamp technique
dc.subjectpharmacophore
dc.subjectprotein conformation
dc.subjectprotein expression
dc.subjectproton nuclear magnetic resonance
dc.subjectstereochemistry
dc.subjectdrug design
dc.subjectHEK293 cell line
dc.subjectmolecular docking
dc.subjectDrug Design
dc.subjectHEK293 Cells
dc.subjectHumans
dc.subjectMolecular Docking Simulation
dc.subjectPotassium Channel Blockers
dc.subjectPotassium Channels, Tandem Pore Domain
dc.titleDiscovery of novel TASK-3 channel blockers using a pharmacophore-based virtual screening
dc.typeArticle


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