scholarly journals Identification and binding mode of a novel Leishmania Trypanothione reductase inhibitor from high throughput screening

2018 ◽  
Vol 12 (11) ◽  
pp. e0006969 ◽  
Author(s):  
Lorenzo Turcano ◽  
Esther Torrente ◽  
Antonino Missineo ◽  
Matteo Andreini ◽  
Marina Gramiccia ◽  
...  
Keyword(s):  
High Throughput ◽  
High Throughput Screening ◽  
Reductase Inhibitor ◽  
Binding Mode ◽  
Trypanothione Reductase

scholarly journals Discovery of 2-iminobenzimidazoles as a new class of trypanothione reductase inhibitor by high-throughput screening

2007 ◽  
Vol 17 (5) ◽  
pp. 1422-1427 ◽  
Author(s):  
Georgina A. Holloway ◽  
Jonathan B. Baell ◽  
Alan H. Fairlamb ◽  
Patrizia M. Novello ◽  
John P. Parisot ◽  
...  
Keyword(s):  
High Throughput ◽  
High Throughput Screening ◽  
Reductase Inhibitor ◽  
Trypanothione Reductase ◽  
New Class

scholarly journals High-throughput Screening and Sensitized Bacteria Identify an M. tuberculosis Dihydrofolate Reductase Inhibitor with Whole Cell Activity

PLoS ONE ◽  
2012 ◽  
Vol 7 (6) ◽  
pp. e39961 ◽  
Author(s):  
Anuradha Kumar ◽  
Meng Zhang ◽  
Linyun Zhu ◽  
Reiling P. Liao ◽  
Charles Mutai ◽  
...  
Keyword(s):  
High Throughput ◽  
Dihydrofolate Reductase ◽  
High Throughput Screening ◽  
Reductase Inhibitor ◽  
Cell Activity ◽  
Whole Cell

scholarly journals A High-Throughput Screening Triage Workflow to Authenticate a Novel Series of PFKFB3 Inhibitors

2017 ◽  
Vol 23 (1) ◽  
pp. 11-22
Author(s):  
Stephen A. St-Gallay ◽  
Neil Bennett ◽  
Susan E. Critchlow ◽  
Nicola Curtis ◽  
Gareth Davies ◽  
...  
Keyword(s):  
High Throughput ◽  
High Throughput Screening ◽  
Isothermal Calorimetry ◽  
Binding Mode ◽  
Carbonyl Oxygen ◽  
Enzyme Concentration ◽  
Titration Calorimetry ◽  
X Ray ◽  
X Ray Crystallography ◽  
The Hill

A high-throughput screen (HTS) of human 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) resulted in several series of compounds with the potential for further optimization. Informatics was used to identify active chemotypes with lead-like profiles and remove compounds that commonly occurred as actives in other HTS screens. The activities were confirmed with IC50 measurements from two orthogonal assay technologies, and further analysis of the Hill slopes and comparison of the ratio of IC50 values at 10 times the enzyme concentration were used to identify artifact compounds. Several series of compounds were rejected as they had both high slopes and poor ratios. A small number of compounds representing the different leading series were assessed using isothermal titration calorimetry, and the X-ray crystal structure of the complex with PFKFB3 was solved. The orthogonal assay technology and isothermal calorimetry were demonstrated to be unreliable in identifying false-positive compounds in this case. Presented here is the discovery of the dihydropyrrolopyrimidinone series of compounds as active and novel inhibitors of PFKFB3, shown by X-ray crystallography to bind to the adenosine triphosphate site. The crystal structures of this series also reveal it is possible to flip the binding mode of the compounds, and the alternative orientation can be driven by a sigma-hole interaction between an aromatic chlorine atom and a backbone carbonyl oxygen. These novel inhibitors will enable studies to explore the role of PFKFB3 in driving the glycolytic phenotype of tumors.

scholarly journals Trypanothione Reductase High-Throughput Screening Campaign Identifies Novel Classes of Inhibitors with Antiparasitic Activity

2009 ◽  
Vol 53 (7) ◽  
pp. 2824-2833 ◽  
Author(s):  
Georgina A. Holloway ◽  
William N. Charman ◽  
Alan H. Fairlamb ◽  
Reto Brun ◽  
Marcel Kaiser ◽  
...  
Keyword(s):  
High Throughput ◽  
High Throughput Screening ◽  
Structure Activity Relationship ◽  
Activity Relationship ◽  
Trypanothione Reductase ◽  
Antiparasitic Activity ◽  
Class A ◽  
Structure Activity ◽  
Metabolic Properties

ABSTRACT High-throughput screening of 100,000 lead-like compounds led to the identification of nine novel chemical classes of trypanothione reductase (TR) inhibitors worthy of further investigation. Hits from five of these chemical classes have been developed further through different combinations of preliminary structure-activity relationship rate probing and assessment of antiparasitic activity, cytotoxicity, and chemical and in vitro metabolic properties. This has led to the identification of novel TR inhibitor chemotypes that are drug-like and display antiparasitic activity. For one class, a series of analogues have displayed a correlation between TR inhibition and antiparasitic activity. This paper explores the process of identifying, investigating, and evaluating a series of hits from a high-throughput screening campaign.

A Qualified Success: Discovery of a New Series of ATAD2 Bromodomain Inhibitors with a Novel Binding Mode Using High-Throughput Screening and Hit Qualification

2019 ◽  
Vol 62 (16) ◽  
pp. 7506-7525 ◽  
Author(s):  
Paul Bamborough ◽  
Chun-wa Chung ◽  
Emmanuel H. Demont ◽  
Angela M. Bridges ◽  
Peter D. Craggs ◽  
...  
Keyword(s):  
High Throughput ◽  
High Throughput Screening ◽  
Binding Mode

High-throughput screening program for botanical extracts

Planta Medica ◽  
2012 ◽  
Vol 78 (11) ◽  
Author(s):  
L Hingorani ◽  
NP Seeram ◽  
B Ebersole
Keyword(s):  
High Throughput ◽  
High Throughput Screening ◽  
Screening Program ◽  
Botanical Extracts

High throughput screening of microbial biodiversity for the discovery of novel cosmeceutical agents

Planta Medica ◽  
2015 ◽  
Vol 81 (16) ◽  
Author(s):  
K Georgousaki ◽  
N DePedro ◽  
AM Chinchilla ◽  
N Aliagiannis ◽  
F Vicente ◽  
...  
Keyword(s):  
High Throughput ◽  
High Throughput Screening ◽  
Microbial Biodiversity

High throughput screening to investigate Brazilian Cerrado biome plant extract bank chemical diversity

Planta Medica ◽  
2016 ◽  
Vol 81 (S 01) ◽  
pp. S1-S381
Author(s):  
LS Espindola ◽  
RG Dusi ◽  
KR Gustafson ◽  
J McMahon ◽  
JA Beutler
Keyword(s):  
High Throughput ◽  
Plant Extract ◽  
High Throughput Screening ◽  
Chemical Diversity ◽  
Brazilian Cerrado ◽  
Cerrado Biome
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