Discovery of Novel TASK-3 Channel Blockers Using a Pharmacophore-Based Virtual Screening
Abstract
TASK-3 is a two-pore domain potassium (K-2P) 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 mu M. Using DR16 as a scaffold, we designed DR16.1, a novel TASK-3 inhibitor, with an IC50 = 14.2 +/- 3.4 mu 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.
Más información
Título según WOS: | Discovery of Novel TASK-3 Channel Blockers Using a Pharmacophore-Based Virtual Screening |
Título según SCOPUS: | Discovery of novel TASK-3 channel blockers using a pharmacophore-based virtual screening |
Título de la Revista: | INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES |
Volumen: | 20 |
Número: | 16 |
Editorial: | MDPI Open Access Publishing |
Fecha de publicación: | 2019 |
Idioma: | English |
DOI: |
10.3390/ijms20164014 |
Notas: | ISI, SCOPUS |