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


ABSTRACT: 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 ?M. Using DR16 as a scaffold, we designed DR16.1, a novel TASK-3 inhibitor, with an IC50 = 14.2 ± 3.4 ?M. 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.

SUBMITTER: Ramirez D 

PROVIDER: S-EPMC6720600 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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

Ramírez David D   Concha Guierdy G   Arévalo Bárbara B   Prent-Peñaloza Luis L   Zúñiga Leandro L   Kiper Aytug K AK   Rinné Susanne S   Reyes-Parada Miguel M   Decher Niels N   Decher Niels N   González Wendy W   Caballero Julio J  

International journal of molecular sciences 20190817 16


TASK-3 is a two-pore domain potassium (K<sub>2P</sub>) 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 phar  ...[more]

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