| Autor: |
David Ramírez, Guierdy Concha, Bárbara Arévalo, Luis Prent-Peñaloza, Leandro Zúñiga, Aytug K. Kiper, Susanne Rinné, Miguel Reyes-Parada, Niels Decher, Wendy González, Julio Caballero |
| Jazyk: |
angličtina |
| Rok vydání: |
2019 |
| Předmět: |
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| Zdroj: |
International Journal of Molecular Sciences, Vol 20, Iss 16, p 4014 (2019) |
| Druh dokumentu: |
article |
| ISSN: |
1422-0067 |
| DOI: |
10.3390/ijms20164014 |
| Popis: |
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. |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
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