scholarly journals High-throughput Screening for Small-molecule Modulators of Inward Rectifier Potassium Channels

10.3791/4209 ◽  
2013 ◽  
Author(s):  
Rene Raphemot ◽  
C. David Weaver ◽  
Jerod S. Denton
Keyword(s):  
Potassium Channels ◽  
Small Molecule ◽  
High Throughput ◽  
High Throughput Screening ◽  
Inward Rectifier ◽  
Inward Rectifier Potassium Channels ◽  
Small Molecule Modulators

scholarly journals Identification of Small Molecule Modulators of Diguanylate Cyclase by FRET-based High-Throughput-Screening

2018 ◽  
Author(s):  
Matthias Christen ◽  
Cassandra Kamischke ◽  
Hemantha D. Kulasekara ◽  
Kathleen C. Olivas ◽  
Bridget R. Kulasekara ◽  
...  
Keyword(s):  
Small Molecules ◽  
Small Molecule ◽  
High Throughput ◽  
Biofilm Formation ◽  
High Throughput Screening ◽  
Diguanylate Cyclase ◽  
Chronic Infections ◽  
Structure Activity ◽  
Diguanylate Cyclases ◽  
Small Molecule Modulators

The bacterial second messenger cyclic diguanosine monophosphate (c-di-GMP) is a key regulator of cellular motility, the cell cycle, and biofilm formation with its resultant antibiotic tolerance, which may make chronic infections difficult to treat. Therefore, diguanylate cyclases, which regulate the spatiotemporal production of c-di-GMP, may be attractive drug targets to control biofilm formation that is part of chronic infections. In this paper, we present a FRET-based biochemical high-throughput screening approach coupled with detailed structure-activity studies to identify synthetic small molecule modulators of the diguanylate cyclase, DgcA, from Caulobacter crescentus. We identified a set of 7 small molecules that in the low µM range regulate DgcA enzymatic activity. Subsequent structure activity studies on selected scaffolds revealed a remarkable diversity of modulatory behaviors, including slight chemical substitutions that revert the effects from allosteric enzyme inhibition to activation. The compounds identified represent novel chemotypes and are potentially developable into chemical genetic tools for the dissection of c-di-GMP signaling networks and alteration of c-di-GMP associated phenotypes. In sum, our studies underline the importance for detailed mechanism of action studies for inhibitors of c-di-GMP signaling and demonstrate the complex interplay between synthetic small molecules and the regulatory mechanisms that control the activity of diguanylate cyclases.

scholarly journals Identification of Small‐Molecule Modulators of Diguanylate Cyclase by FRET‐Based High‐Throughput Screening

ChemBioChem ◽  
2018 ◽  
Vol 20 (3) ◽  
pp. 394-407 ◽  
Author(s):  
Matthias Christen ◽  
Cassandra Kamischke ◽  
Hemantha D. Kulasekara ◽  
Kathleen C. Olivas ◽  
Bridget R. Kulasekara ◽  
...  
Keyword(s):  
Small Molecule ◽  
High Throughput ◽  
High Throughput Screening ◽  
Diguanylate Cyclase ◽  
Small Molecule Modulators

scholarly journals A Thallium-Sensitive, Fluorescence-Based Assay for Detecting and Characterizing Potassium Channel Modulators in Mammalian Cells

2004 ◽  
Vol 9 (8) ◽  
pp. 671-677 ◽  
Author(s):  
C. David Weaver ◽  
David Harden ◽  
Steven I. Dworetzky ◽  
Barbara Robertson ◽  
Ronald J. Knox
Keyword(s):  
Potassium Channels ◽  
High Throughput ◽  
High Throughput Screening ◽  
Mammalian Cells ◽  
Ease Of Use ◽  
Functional Assay ◽  
Chemical Libraries ◽  
Potassium Channel Modulators ◽  
Small Molecule Modulators

Potassium channels have been identified as targets for a large number of therapeutic indications. The ability to use a high-throughput functional assay for the detection and characterization of small-molecule modulators of potassium channels is very desirable. However, present techniques capable of screening very large chemical libraries are limited in terms of data quality, temporal resolution, ease of use, and requirements for specialized instrumentation. To address these issues, the authors have developed a fluorescence-based thalliumflux assay. This assay is capable of detectingmodulators of both voltageand ligand-gated potassium channels expressed inmammalian cells. The thalliumflux assay can use instruments standard to most high-throughput screening laboratories, and using such equipment has been successfully employed to screen large chemical libraries consisting of hundreds of thousands of compounds.

High‐throughput screening reveals small molecule modulators inhibitory to Acidovorax citrulli

2020 ◽  
Vol 69 (5) ◽  
pp. 818-826
Author(s):  
Yu Lu ◽  
Loïc Deblais ◽  
Gireesh Rajashekara ◽  
Sally A. Miller ◽  
Yorsa A. Helmy ◽  
...  
Keyword(s):  
Small Molecule ◽  
High Throughput ◽  
High Throughput Screening ◽  
Acidovorax Citrulli ◽  
Small Molecule Modulators

High-Throughput Screening for Small Molecule Modulators of FGFR2-IIIb Pre-mRNA Splicing

2012 ◽  
pp. 127-138
Author(s):  
Erik S. Anderson ◽  
Peter Stoilov ◽  
Robert Damoiseaux ◽  
Douglas L. Black
Keyword(s):  
Small Molecule ◽  
High Throughput ◽  
High Throughput Screening ◽  
Mrna Splicing ◽  
Small Molecule Modulators
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