Details

Autor(en) / Beteiligte

• Ramírez, David
• Concha, Guierdy
• Arévalo, Bárbara
• Prent-Peñaloza, Luis
• Zúñiga, Leandro
• Kiper, Aytug K
• Rinné, Susanne
• Reyes-Parada, Miguel
• Decher, Niels
• González, Wendy
• Caballero, Julio

Titel

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

Ist Teil von

• International journal of molecular sciences, 2019-08, Vol.20 (16), p.4014

Ort / Verlag

Switzerland: MDPI AG

Erscheinungsjahr

2019

Link zum Volltext

Quelle

MEDLINE

Beschreibungen/Notizen

• TASK-3 is a two-pore domain potassium (K ) 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 ( ) was identified with an IC = 56.8 ± 3.9 μM. Using as a scaffold, we designed , a novel TASK-3 inhibitor, with an IC = 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 ( and ) are the first compounds found using a pharmacophore-based virtual screening and rational drug design protocol.