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Structure/activity analysis of task-3 channel antagonists based on a 5,6,7,8 tetrahydropyrido[4,3-d]pyrimidine

dc.contributor.authorRamírez D.
dc.contributor.authorBedoya M.
dc.contributor.authorKiper A.K.
dc.contributor.authorRinné S.
dc.contributor.authorMorales-Navarro S.
dc.contributor.authorHernández-Rodríguez E.W.
dc.contributor.authorSepúlveda F.V.
dc.contributor.authorDecher N.
dc.contributor.authorGonzález W.
dc.date.accessioned2020-09-02T22:26:31Z
dc.date.available2020-09-02T22:26:31Z
dc.date.issued2019
dc.identifier10.3390/ijms20092252
dc.identifier.citation20, 9, -
dc.identifier.issn16616596
dc.identifier.urihttps://hdl.handle.net/20.500.12728/5947
dc.descriptionTASK-3 potassium (K+) channels are highly expressed in the central nervous system, regulating the membrane potential of excitable cells. TASK-3 is involved in neurotransmitter action and has been identified as an oncogenic K+ channel. For this reason, the understanding of the action mechanism of pharmacological modulators of these channels is essential to obtain new therapeutic strategies. In this study we describe the binding mode of the potent antagonist PK-THPP into the TASK-3 channel. PK-THPP blocks TASK-1, the closest relative channel of TASK-3, with almost nine-times less potency. Our results confirm that the binding is influenced by the fenestrations state of TASK-3 channels and occurs when they are open. The binding is mainly governed by hydrophobic contacts between the blocker and the residues of the binding site. These interactions occur not only for PK-THPP, but also for the antagonist series based on 5,6,7,8 tetrahydropyrido[4,3-d]pyrimidine scaffold (THPP series). However, the marked difference in the potency of THPP series compounds such as 20b, 21, 22 and 23 (PK-THPP) respect to compounds such as 17b, inhibiting TASK-3 channels in the micromolar range is due to the presence of a hydrogen bond acceptor group that can establish interactions with the threonines of the selectivity filter. © 2019 by the authors. Licensee MDPI, Basel, Switzerland.
dc.language.isoen
dc.publisherMDPI AG
dc.subject5,6,7,8 tetrahydropyrido[4,3-d]pyrimidine derivatives
dc.subjectDrug-protein interaction
dc.subjectMolecular docking
dc.subjectMolecular dynamics
dc.subjectMutagenesis screen
dc.subjectPk-thpp
dc.subjectTask channels blockers
dc.subjectTASK-3 channel
dc.subject5,6,7,8 tetrahydropyrido [4,3 d] pyrimidine
dc.subjectneurotransmitter
dc.subjectpotassium channel blocking agent
dc.subjectpyrimidine derivative
dc.subjecttask 3 channel
dc.subjectthreonine
dc.subjectunclassified drug
dc.subjectKCNK9 protein, human
dc.subjectpotassium channel blocking agent
dc.subjectprotein binding
dc.subjectpyridine derivative
dc.subjectpyrimidine derivative
dc.subjecttandem pore domain potassium channel
dc.subjecttetrahydropyrido(4,3-d)pyrimidine
dc.subjectArticle
dc.subjectbinding affinity
dc.subjectbinding site
dc.subjectchemical interaction
dc.subjectconformational transition
dc.subjectdrug binding site
dc.subjectelectrophysiology
dc.subjectentropy
dc.subjectfenestration
dc.subjecthydrogen bond
dc.subjectIC50
dc.subjectlipophilicity
dc.subjectmembrane potential
dc.subjectmolecular docking
dc.subjectmolecular dynamics
dc.subjectmolecular mechanics
dc.subjectmutagenesis
dc.subjectnonhuman
dc.subjectpharmacophore
dc.subjectprotein interaction
dc.subjectreceptor binding
dc.subjectrelative binding affinity
dc.subjectsequence alignment
dc.subjectsteady state
dc.subjectstructure activity relation
dc.subjectstructure analysis
dc.subjecttwo dimensional quantitative structure activity relationship
dc.subjectXenopus laevis
dc.subjectanimal
dc.subjectantagonists and inhibitors
dc.subjectchemistry
dc.subjecthuman
dc.subjectmolecular docking
dc.subjectXenopus
dc.subjectAnimals
dc.subjectBinding Sites
dc.subjectHumans
dc.subjectMolecular Docking Simulation
dc.subjectPotassium Channel Blockers
dc.subjectPotassium Channels, Tandem Pore Domain
dc.subjectProtein Binding
dc.subjectPyridines
dc.subjectPyrimidines
dc.subjectXenopus
dc.titleStructure/activity analysis of task-3 channel antagonists based on a 5,6,7,8 tetrahydropyrido[4,3-d]pyrimidine
dc.typeArticle


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