scholarly journals Selective Small Molecule Targeting β-Catenin Function Discovered by In Vivo Chemical Genetic Screen

Cell Reports ◽  
2013 ◽  
Vol 4 (5) ◽  
pp. 898-904 ◽  
Author(s):  
Jijun Hao ◽  
Ada Ao ◽  
Li Zhou ◽  
Clare K. Murphy ◽  
Audrey Y. Frist ◽  
...  
Keyword(s):  
Small Molecule ◽  
Genetic Screen ◽  
Chemical Genetic

scholarly journals Conserved lipid and small molecule modulation of COQ8 reveals regulation of the ancient UbiB family

2017 ◽  
Author(s):  
Andrew G. Reidenbach ◽  
Zachary A. Kemmerer ◽  
Deniz Aydin ◽  
Adam Jochem ◽  
Molly T. McDevitt ◽  
...  
Keyword(s):  
Small Molecule ◽  
Coenzyme Q ◽  
Genetic System ◽  
Direct Role ◽  
Chemical Genetic ◽  
Evolutionarily Conserved ◽  
Endogenous Regulators ◽  
Endogenous Activity ◽  
Small Molecule Modulators

SummaryHuman COQ8A (ADCK3) and Saccharomyces cerevisiae Coq8p (collectively COQ8) are UbiB family proteins essential for mitochondrial coenzyme Q (CoQ) biosynthesis. However, the biochemical activity of COQ8 and its direct role in CoQ production remain unclear, in part due to lack of known endogenous regulators of COQ8 function and of effective small molecules for probing its activity in vivo. Here we demonstrate that COQ8 possesses evolutionarily conserved ATPase activity that is activated by binding to membranes containing cardiolipin and by phenolic compounds that resemble CoQ pathway intermediates. We further create an analog-sensitive version of Coq8p and reveal that acute chemical inhibition of its endogenous activity in yeast is sufficient to cause respiratory deficiency concomitant with CoQ depletion. Collectively, this work defines lipid and small molecule modulators of an ancient family of atypical kinase-like proteins and establishes a chemical genetic system for further exploring the mechanistic role of COQ8 in CoQ biosynthesis.

scholarly journals An In Vivo Chemical Genetic Screen Identifies Phosphodiesterase 4 as a Pharmacological Target for Hedgehog Signaling Inhibition

Cell Reports ◽  
2015 ◽  
Vol 11 (1) ◽  
pp. 43-50 ◽  
Author(s):  
Charles H. Williams ◽  
Jonathan E. Hempel ◽  
Jijun Hao ◽  
Audrey Y. Frist ◽  
Michelle M. Williams ◽  
...  
Keyword(s):  
Hedgehog Signaling ◽  
Genetic Screen ◽  
Chemical Genetic ◽  
Phosphodiesterase 4 ◽  
Pharmacological Target

scholarly journals Prieurianin/endosidin 1 is an actin-stabilizing small molecule identified from a chemical genetic screen for circadian clock effectors in Arabidopsis thaliana

2012 ◽  
Vol 71 (2) ◽  
pp. 338-352 ◽  
Author(s):  
Réka Tóth ◽  
Claas Gerding-Reimers ◽  
Michael J. Deeks ◽  
Sascha Menninger ◽  
Rafael M. Gallegos ◽  
...  
Keyword(s):  
Arabidopsis Thaliana ◽  
Circadian Clock ◽  
Small Molecule ◽  
Genetic Screen ◽  
Chemical Genetic

120-LB: Small Molecule Activator of Pyruvate Kinase Regulates In Vivo Glucose Homeostasis

Diabetes ◽  
2020 ◽  
Vol 69 (Supplement 1) ◽  
pp. 120-LB
Author(s):  
ABUDUKADIER ABULIZI ◽  
REBECCA L. CARDONE ◽  
STEPHAN SIEBEL ◽  
CHARLES KUNG ◽  
RICHARD KIBBEY
Keyword(s):  
Pyruvate Kinase ◽  
Small Molecule ◽  
Glucose Homeostasis

Quantitative Ranking of Ligand Binding Kinetics with a Multiscale Milestoning Simulation Approach

2018 ◽  
Author(s):  
Benjamin R. Jagger ◽  
Christoper T. Lee ◽  
Rommie Amaro
Keyword(s):  
Molecular Dynamics ◽  
Drug Discovery ◽  
Small Molecule ◽  
Brownian Dynamics ◽  
Model Simulation ◽  
Computational Cost ◽  
Lead Selection ◽  
Delta G ◽  
Dynamics Simulations

<p>The ranking of small molecule binders by their kinetic (kon and koff) and thermodynamic (delta G) properties can be a valuable metric for lead selection and optimization in a drug discovery campaign, as these quantities are often indicators of in vivo efficacy. Efficient and accurate predictions of these quantities can aid the in drug discovery effort, acting as a screening step. We have previously described a hybrid molecular dynamics, Brownian dynamics, and milestoning model, Simulation Enabled Estimation of Kinetic Rates (SEEKR), that can predict kon’s, koff’s, and G’s. Here we demonstrate the effectiveness of this approach for ranking a series of seven small molecule compounds for the model system, -cyclodextrin, based on predicted kon’s and koff’s. We compare our results using SEEKR to experimentally determined rates as well as rates calculated using long-timescale molecular dynamics simulations and show that SEEKR can effectively rank the compounds by koff and G with reduced computational cost. We also provide a discussion of convergence properties and sensitivities of calculations with SEEKR to establish “best practices” for its future use.</p>

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