In Silico Small Molecular Docking to Task-1 Channel Structure
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Joana Lopez
CoPIs:
Abena Amankwee, Diego Chavez, Justin Patino, Yara Farrag, Steven Almazan, David Graham, Megan Blaisdell, Gianna Medeiros, Rinchu George, Chelsea Pelley, Ana Dumani, Melanie Marano, Marilyn Dennis, Jonelle Brown
College:
The Dorothy and George Hennings College of Science, Mathematics, and Technology
Major:
Biology
Faculty Research Advisor(s):
Thomas Comollo
Abstract:
KU124 AS A NOVEL TASK1 INHIBITOR
TASK-1 stands for TWIK-related acid sensitive potassium channel 1 and is encoded by the KCNK3 gene. It is a member of the two-pore potassium (K + ) channel family. TASK-1 channels are expressed in humans and modulate cell excitability in excitable cells such as neurons, cardiomyocytes, and vascular smooth muscle cells. TASK-1 channels have also been shown to play a crucial role in circumventing cell apoptosis in a population of non-small cell lung cancer cells. We propose that the inner vestibule of the TASK 1 channel, a known binding site of known TASK inhibitors, BAY10000493 and BAY2341237, can be exploited to find other TASK-1 inhibitors as well.
We employed virtual screening / small molecule docking methodologies targeting this inner vestibule binding site. Following an initial screening of ~900,000 small molecules from the ZINC12 data base we purchased three selected, good scoring small molecules for testing in a Thallium Flux assay utilizing an inducible TASK-1-GFP expressing CHO cell line (a generous gift from Dr, Douglas Bayliss, University of Virginia). We used doxapram sensitivity as a readout of TASK-1 conductance. KU124 is what we have deemed one of our selected molecules. In our initial testing it appears to inhibit doxapram sensitive TASK-1 conductance; possibly with a sub micromolar IC50.
Our results show that the inner vestibule site can be exploited to find additional TASK-1 inhibitors and validate our virtual screening methodology. In this research study, we are currently seeking to identify additional drug like small molecules predicted to inhibit TASK-1 channel conductance using in silico small molecule docking simulations / virtual screen as well as verify the ability of selected small molecules to inhibit TASK-1 channel conductance in vitro assays.