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 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.
Highlights
Two-pore domain potassium (K2P) channels have a major role in the regulation of cell excitability and membrane potential in excitable and non-excitable cells [1]
Analysis of the different fenestration states in T3-trCO (Figure S1B) shows how the hydrophobic interactions between Leu239 (TM4 segment) with Leu197 (TM2 segment) and Val115, as well as between Ile235 (TM4 segment) with Leu197 and Val115, modulate the fenestration opening–closing mechanism. These interactions are in concordance with the results presented by Brohawn et al [14], where the residues Leu151, Leu236, Ile279, and Leu283 of TRAAK are implicated in the opening–closing mechanism of the TRAAK fenestration [41] (TASK-3 residues Val115, Leu197, Ile235, and Leu239 are equivalent to TRAAK residues Leu151, Leu236, Ile279, and Leu283, respectively)
The model names are: T3-treCC (TASK-3 built from TREK-2 in Close-Close fenestration state), T3-twiOO (TASK-3 built from TWIK-1 in Open-Open fenestration state), T3-trCO (TASK-3 built from TRAAK in Close-Open fenestration state), and T3-trOO (TASK-3 built from TRAAK in Open-Open fenestration state)
Summary
Two-pore domain potassium (K2P) channels have a major role in the regulation of cell excitability and membrane potential in excitable and non-excitable cells [1]. Some studies have demonstrated that TASK channels participate in the chemical control of breathing due to their intrinsic pH and O2 sensitivity [7–9]. These channels are expressed in the nervous, cardiovascular, genitourinary, and gastrointestinal systems [10]. They are involved in chemosensation [11] and have a role in the regulation of the immune system [12]. TASK channels are acid-sensitive and anesthetic-activated members of the K2P family They contribute to the effects of general anesthetics due to the activation of background K+ currents causing a decrease of excitability by neuronal hyperpolarization [13], which makes these channels prominent molecular targets for these drugs
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