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Int J Mol Sci. 2019 May 7;20(9). pii: E2252. doi: 10.3390/ijms20092252.

Structure/Activity Analysis of TASK-3 Channel Antagonists Based on a 5,6,7,8 tetrahydropyrido[4,3-d]pyrimidine.

Author information

1
Instituto de Ciencias Biomédicas, Facultad de Ciencias de la Salud, Universidad Autónoma de Chile. El Llano Subercaseaux 2801-Piso 6, 7500912 Santiago, Chile. david.ramirez@uautonoma.cl.
2
Centro de Bioinformática y Simulación Molecular (CBSM), Universidad de Talca. 1 Poniente No. 1141, 3460000 Talca, Chile. maurobedoyat@gmail.com.
3
Institute for Physiology and Pathophysiology, Vegetative Physiology, Philipps-University of Marburg, Deutschhausstraße 2, 35037 Marburg, Germany. aytug.kiper@staff.uni-marburg.de.
4
Institute for Physiology and Pathophysiology, Vegetative Physiology, Philipps-University of Marburg, Deutschhausstraße 2, 35037 Marburg, Germany. rinne@staff.uni-marburg.de.
5
Bachillerato en Ciencias, Facultad de Ciencias, Universidad Santo Tomás, Av. Circunvalación Poniente #1855, 3460000 Talca, Chile. smoralesn@santotomas.cl.
6
Centro de Bioinformática y Simulación Molecular (CBSM), Universidad de Talca. 1 Poniente No. 1141, 3460000 Talca, Chile. erhernandez@utalca.cl.
7
Escuela de Química y Farmacia. Facultad de Medicina. Universidad Católica del Maule, 3460000 Talca, Chile. erhernandez@utalca.cl.
8
Centro de Estudios Científicos (CECs), Arturo Prat 514, 5110000 Valdivia, Chile. fsepulveda@cecs.cl.
9
Institute for Physiology and Pathophysiology, Vegetative Physiology, Philipps-University of Marburg, Deutschhausstraße 2, 35037 Marburg, Germany. decher@staff.uni-marburg.de.
10
Centro de Bioinformática y Simulación Molecular (CBSM), Universidad de Talca. 1 Poniente No. 1141, 3460000 Talca, Chile. wgonzalez@utalca.cl.
11
Millennium Nucleus of Ion Channels-Associated Diseases (MiNICAD), Universidad de Talca, 3460000 Talca, Chile. wgonzalez@utalca.cl.

Abstract

TASK-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.

KEYWORDS:

5,6,7,8 tetrahydropyrido[4,3-d]pyrimidine derivatives; PK-THPP; TASK channels blockers; TASK-3 channel; drug-protein interaction; molecular docking; molecular dynamics; mutagenesis screen

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