A random small molecule library screen identifies novel antagonists of the kinin receptor from the cattle fever tick, Rhipicephalus microplus (Acari: Ixodidae)

2021 ◽  
Author(s):  
Caixing Xiong ◽  
Dwight Baker ◽  
Patricia V Pietrantonio
Keyword(s):  
Small Molecule ◽  
Rhipicephalus Microplus ◽  
Small Molecule Library ◽  
Kinin Receptor ◽  
Library Screen ◽  
Cattle Fever Tick

Inhibition of NGLY1 inactivates the transcription factor Nrf1 and potentiates proteasome inhibitor cytotoxicity

2017 ◽  
Author(s):  
Carolyn Bertozzi ◽  
Fred Tomlin ◽  
Ulla Gerling-Driessen ◽  
Yi-Chang Liu ◽  
Ryan Flynn ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Small Molecule ◽  
Proteasome Inhibitor ◽  
Activation Mechanism ◽  
Cancer Drugs ◽  
Small Molecule Library ◽  
Library Screen ◽  
In Cells

We discovered that the proteostasis modulating transcription factor Nrf1 requires cytosolic de-N-glycosylation by the N-glycanase NGly1 as part of its activation mechanism. Through a covalent small molecule library screen, we discovered an inhibitor of NGly1 that blocks Nrf1 activation in cells and potentiates the activity of proteasome inhibitor cancer drugs. The requirement of NGly1 for Nrf1 activity likely underlies several pathologies associated with a rare hereditary deficiency in NGly1.

Inhibition of NGLY1 inactivates the transcription factor Nrf1 and potentiates proteasome inhibitor cytotoxicity

2017 ◽  
Author(s):  
Carolyn Bertozzi ◽  
Fred Tomlin ◽  
Ulla Gerling-Driessen ◽  
Yi-Chang Liu ◽  
Ryan Flynn ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Small Molecule ◽  
Proteasome Inhibitor ◽  
Activation Mechanism ◽  
Cancer Drugs ◽  
Small Molecule Library ◽  
Library Screen ◽  
In Cells

We discovered that the proteostasis modulating transcription factor Nrf1 requires cytosolic de-N-glycosylation by the N-glycanase NGly1 as part of its activation mechanism. Through a covalent small molecule library screen, we discovered an inhibitor of NGly1 that blocks Nrf1 activation in cells and potentiates the activity of proteasome inhibitor cancer drugs. The requirement of NGly1 for Nrf1 activity likely underlies several pathologies associated with a rare hereditary deficiency in NGly1.

scholarly journals Evaluation of ethyl N-(2-phenethyl) carbamate analogues as biofilm inhibitors of methicillin resistant Staphylococcus aureus

2016 ◽  
Vol 14 (28) ◽  
pp. 6853-6856 ◽  
Author(s):  
Matthew D. Stephens ◽  
Nisakorn Yodsanit ◽  
Christian Melander
Keyword(s):  
Staphylococcus Aureus ◽  
Small Molecule ◽  
Broad Spectrum ◽  
Biofilm Formation ◽  
Methicillin Resistant Staphylococcus Aureus ◽  
Methicillin Resistant ◽  
Small Molecule Library

A small molecule library consisting of 45 compounds was synthesized based on the bacterial metabolite ethylN-(2-phenethyl) carbamate. From this library, a more potent, broad-spectrum inhibitor of MRSA biofilm formation was discovered.

scholarly journals CHI PMUNK: A Virtual Synthesizable Small-Molecule Library for Medicinal Chemistry, Exploitable for Protein-Protein Interaction Modulators

ChemMedChem ◽  
2018 ◽  
Vol 13 (6) ◽  
pp. 532-539 ◽  
Author(s):  
Lina Humbeck ◽  
Sebastian Weigang ◽  
Till Schäfer ◽  
Petra Mutzel ◽  
Oliver Koch
Keyword(s):  
Small Molecule ◽  
Protein Interaction ◽  
Medicinal Chemistry ◽  
Protein Protein Interaction ◽  
Small Molecule Library

scholarly journals Discovery of PqsE Thioesterase Inhibitors for Pseudomonas aeruginosa Using DNA-Encoded Small Molecule Library Screening

2019 ◽  
Vol 15 (2) ◽  
pp. 446-456 ◽  
Author(s):  
Julie S. Valastyan ◽  
Michael R. Tota ◽  
Isabelle R. Taylor ◽  
Vasiliki Stergioula ◽  
Graham A. B. Hone ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Small Molecule ◽  
Library Screening ◽  
Small Molecule Library

scholarly journals Deep-learning-based target screening and similarity search for the predicted inhibitors of the pathways in Parkinson's disease

RSC Advances ◽  
2019 ◽  
Vol 9 (18) ◽  
pp. 10326-10339 ◽  
Author(s):  
Abbas Khan ◽  
Aman Chandra Kaushik ◽  
Syed Shujait Ali ◽  
Nisar Ahmad ◽  
Dong-Qing Wei
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Deep Learning ◽  
Small Molecule ◽  
Similarity Search ◽  
De Novo ◽  
Learning Method ◽  
Small Molecule Library ◽  
Target Screening

Herein, a two-step de novo approach was developed for the prediction of piperine targets and another prediction of similar (piperine) compounds from a small molecule library using a deep-learning method.

scholarly journals Allosteric “beta-blocker” isolated from a DNA-encoded small molecule library

2017 ◽  
Vol 114 (7) ◽  
pp. 1708-1713 ◽  
Author(s):  
Seungkirl Ahn ◽  
Alem W. Kahsai ◽  
Biswaranjan Pani ◽  
Qin-Ting Wang ◽  
Shuai Zhao ◽  
...  
Keyword(s):  
Binding Site ◽  
G Protein ◽  
Small Molecule ◽  
Adrenergic Receptor ◽  
Camp Production ◽  
Small Molecule Library ◽  
Small Molecule Libraries ◽  
Negative Allosteric Modulator ◽  
G Protein Coupled ◽  
Small Molecule Ligand

The β2-adrenergic receptor (β2AR) has been a model system for understanding regulatory mechanisms of G-protein–coupled receptor (GPCR) actions and plays a significant role in cardiovascular and pulmonary diseases. Because all known β-adrenergic receptor drugs target the orthosteric binding site of the receptor, we set out to isolate allosteric ligands for this receptor by panning DNA-encoded small-molecule libraries comprising 190 million distinct compounds against purified human β2AR. Here, we report the discovery of a small-molecule negative allosteric modulator (antagonist), compound 15 [([4-((2S)-3-(((S)-3-(3-bromophenyl)-1-(methylamino)-1-oxopropan-2-yl)amino)-2-(2-cyclohexyl-2-phenylacetamido)-3-oxopropyl)benzamide], exhibiting a unique chemotype and low micromolar affinity for the β2AR. Binding of 15 to the receptor cooperatively enhances orthosteric inverse agonist binding while negatively modulating binding of orthosteric agonists. Studies with a specific antibody that binds to an intracellular region of the β2AR suggest that 15 binds in proximity to the G-protein binding site on the cytosolic surface of the β2AR. In cell-signaling studies, 15 inhibits cAMP production through the β2AR, but not that mediated by other Gs-coupled receptors. Compound 15 also similarly inhibits β-arrestin recruitment to the activated β2AR. This study presents an allosteric small-molecule ligand for the β2AR and introduces a broadly applicable method for screening DNA-encoded small-molecule libraries against purified GPCR targets. Importantly, such an approach could facilitate the discovery of GPCR drugs with tailored allosteric effects.

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