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Article

Discovery of Novel TASK-3 Channel Blockers Using a Pharmacophore-Based Virtual Screening

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Instituto de Ciencias Biomédicas, Facultad de Ciencias de la Salud, Universidad Autónoma de Chile, El Llano Subercaseaux 2801-Piso 5, 8900000 Santiago, Chile
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Centro de Investigaciones Médicas (CIM), Programa de Investigación Asociativa en Cáncer Gástrico (PIA-CG), Escuela de Medicina, Universidad de Talca, 2 Norte 685, 3460000 Talca, Chile
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Informática y Telecomunicaciones, Universidad Tecnológica de Chile Inacap, Sede Talca, Av. San Miguel 3496, 3460000 Talca, Chile
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Organic Synthesis Laboratory and Biological Activity (LSO-Act-Bio), PhD Applied Sciences, Faculty of Engineering, Institute of Chemistry of Natural Resources, Universidad de Talca, 1 Poniente No. 1141, 3460000 Talca, Chile
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Institute for Physiology and Pathophysiology, Vegetative Physiology, Philipps-University of Marburg, Deutschhausstraße 2, 35037 Marburg, Germany
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Centro de Investigación Biomédica y Aplicada (CIBAP), Escuela de Medicina, Facultad de Ciencias Médicas, Universidad de Santiago de Chile, Av. Libertador Bernardo O’Higgins 3677, 8900000 Santiago, Chile
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Facultad de Ciencias de la Salud, Universidad Autónoma de Chile, Avenida Pedro de Valdivia 425, 8900000 Santiago, Chile
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Center for Mind, Brain and Behavior (CMBB), University of Marburg and Justus Liebig University Giessen, 35037 Marburg, Germany
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Centro de Bioinformática y Simulación Molecular (CBSM), Universidad de Talca. 1 Poniente No. 1141, 3460000 Talca, Chile
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Millennium Nucleus of Ion Channels-Associated Diseases (MiNICAD), Universidad de Talca, 3460000 Talca, Chile
*
Authors to whom correspondence should be addressed.
Int. J. Mol. Sci. 2019, 20(16), 4014; https://doi.org/10.3390/ijms20164014
Received: 2 July 2019 / Revised: 6 August 2019 / Accepted: 13 August 2019 / Published: 17 August 2019
(This article belongs to the Section Biochemistry)
TASK-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. View Full-Text
Keywords: TASK-3 channel; drug design; TASK channels blockers; pharmacophore-based virtual screening; lead optimization TASK-3 channel; drug design; TASK channels blockers; pharmacophore-based virtual screening; lead optimization
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MDPI and ACS Style

Ramírez, D.; Concha, G.; Arévalo, B.; Prent-Peñaloza, L.; Zúñiga, L.; Kiper, A.K.; Rinné, S.; Reyes-Parada, M.; Decher, N.; González, W.; Caballero, J. Discovery of Novel TASK-3 Channel Blockers Using a Pharmacophore-Based Virtual Screening. Int. J. Mol. Sci. 2019, 20, 4014. https://doi.org/10.3390/ijms20164014

AMA Style

Ramírez D, Concha G, Arévalo B, Prent-Peñaloza L, Zúñiga L, Kiper AK, Rinné S, Reyes-Parada M, Decher N, González W, Caballero J. Discovery of Novel TASK-3 Channel Blockers Using a Pharmacophore-Based Virtual Screening. International Journal of Molecular Sciences. 2019; 20(16):4014. https://doi.org/10.3390/ijms20164014

Chicago/Turabian Style

Ramírez, David, Guierdy Concha, Bárbara Arévalo, Luis Prent-Peñaloza, Leandro Zúñiga, Aytug K. Kiper, Susanne Rinné, Miguel Reyes-Parada, Niels Decher, Wendy González, and Julio Caballero. 2019. "Discovery of Novel TASK-3 Channel Blockers Using a Pharmacophore-Based Virtual Screening" International Journal of Molecular Sciences 20, no. 16: 4014. https://doi.org/10.3390/ijms20164014

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