In vitro metabolism study of a novel P38 kinase inhibitor: in silico predictions, structure elucidation using MS/MS-I

2018 ◽  
Vol 10 (2) ◽  
pp. 201-220 ◽  
Author(s):  
Hanaa MA Hashem ◽  
Marianne A Mahrouse
Keyword(s):  
In Silico ◽  
Structure Elucidation ◽  
Kinase Inhibitor ◽  
In Vitro Metabolism ◽  
P38 Kinase ◽  
Metabolism Study ◽  
In Silico Predictions

scholarly journals In silico and in vitro pharmacogenetics: aldehyde oxidase rapidly metabolizes a p38 kinase inhibitor

2010 ◽  
Vol 11 (1) ◽  
pp. 15-24 ◽  
Author(s):  
X Zhang ◽  
H-H Liu ◽  
P Weller ◽  
M Zheng ◽  
W Tao ◽  
...  
Keyword(s):  
In Silico ◽  
Kinase Inhibitor ◽  
Aldehyde Oxidase ◽  
P38 Kinase

scholarly journals Identification of Vinyl Sulfone Derivatives as EGFR Tyrosine Kinase Inhibitor: In Vitro and In Silico Studies

Molecules ◽  
2021 ◽  
Vol 26 (8) ◽  
pp. 2211
Author(s):  
Thitinan Aiebchun ◽  
Panupong Mahalapbutr ◽  
Atima Auepattanapong ◽  
Onnicha Khaikate ◽  
Supaphorn Seetaha ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Inhibitory Activity ◽  
In Silico ◽  
Kinase Inhibitor ◽  
Kinase Assay ◽  
Vinyl Sulfone ◽  
Egfr Tyrosine Kinase ◽  
In Silico Studies ◽  
Sulfone Derivatives

Epidermal growth factor receptor (EGFR), overexpressed in many types of cancer, has been proved as a high potential target for targeted cancer therapy due to its role in regulating proliferation and survival of cancer cells. In the present study, a series of designed vinyl sulfone derivatives was screened against EGFR tyrosine kinase (EGFR-TK) using in silico and in vitro studies. The molecular docking results suggested that, among 78 vinyl sulfones, there were eight compounds that could interact well with the EGFR-TK at the ATP-binding site. Afterwards, these screened compounds were tested for the inhibitory activity towards EGFR-TK using ADP-Glo™ kinase assay, and we found that only VF16 compound exhibited promising inhibitory activity against EGFR-TK with the IC50 value of 7.85 ± 0.88 nM. In addition, VF16 showed a high cytotoxicity with IC50 values of 33.52 ± 2.57, 54.63 ± 0.09, and 30.38 ± 1.37 µM against the A431, A549, and H1975 cancer cell lines, respectively. From 500-ns MD simulation, the structural stability of VF16 in complex with EGFR-TK was quite stable, suggesting that this compound could be a novel small molecule inhibitor targeting EGFR-TK.

scholarly journals Phosphorylation of Ser158 regulates inflammatory redox-dependent hepatocyte nuclear factor-4α transcriptional activity

2006 ◽  
Vol 394 (2) ◽  
pp. 379-387 ◽  
Author(s):  
Hongtao Guo ◽  
Chengjiang Gao ◽  
Zhiyong Mi ◽  
Philip Y. Wai ◽  
Paul C. Kuo
Keyword(s):  
Dna Binding ◽  
Kinase Inhibitor ◽  
Critical Role ◽  
Nuclear Factor ◽  
Hepatocyte Nuclear Factor ◽  
P38 Kinase ◽  
Mobility Shift ◽  
Transactivation Potential ◽  
Hepatocyte Nuclear Factor 4Α

In IL-1β (interleukin 1β)-stimulated rat hepatocytes exposed to superoxide, we have previously identified an IRX (inflammatory redox)-sensitive DR1 [direct repeat of RG(G/T)TCA with one base spacing] cis-acting activator element (nt –1327 to –1315) in the iNOS (inducible nitric oxide synthase) promoter: AGGTCAGGGGACA. The corresponding transcription factor was identified to be HNF4α (hepatocyte nuclear factor-4α). HNF4α DNA binding activity and transactivation potential are tightly regulated by its state of phosphorylation. However, the functional consequences of IRX-mediated post-translational phosphorylation of HNF4α have not been well characterized. In the setting of IL-1β+H2O2, HNF4α functional activity is associated with a unique serine/threonine phosphorylation pattern. This indicates that an IRX-sensitive serine/threonine kinase pathway targets HNF4α to augment hepatocyte iNOS transcription. In the present study, following identification of phosphorylated residues in HNF4α, serial mutations were performed to render the target residues phosphorylation-resistant. Electrophoretic mobility-shift assays and transient transfection studies utilizing the iNOS promoter showed that the S158A mutation ablates IRX-mediated HNF4α DNA binding and transactivation. Gain-of-function mutation with the S158D phosphomimetic HNF4α vector supports a critical role for Ser158 phosphorylation. In vitro phosphorylation and kinase inhibitor studies implicate p38 kinase activity. Our results indicate that p38 kinase-mediated Ser158 phosphorylation is essential for augmentation of the DNA binding and transactivation potential of HNF4α in the presence of IL-1β+H2O2. This pathway results in enhanced iNOS expression in hepatocytes exposed to pro-inflammatory cytokines and oxidative stress.

scholarly journals Enone– and Chalcone–Chloroquinoline Hybrid Analogues: In Silico Guided Design, Synthesis, Antiplasmodial Activity, in Vitro Metabolism, and Mechanistic Studies

2011 ◽  
Vol 54 (10) ◽  
pp. 3637-3649 ◽  
Author(s):  
Eric M. Guantai ◽  
Kanyile Ncokazi ◽  
Timothy J. Egan ◽  
Jiri Gut ◽  
Philip J. Rosenthal ◽  
...  
Keyword(s):  
In Silico ◽  
In Vitro Metabolism ◽  
Antiplasmodial Activity ◽  
Mechanistic Studies ◽  
Design Synthesis

IN VITRO METABOLISM OF THE PHOSPHATIDYLINOSITOL 3-KINASE INHIBITOR, WORTMANNIN, BY CARBONYL REDUCTASE

2004 ◽  
Vol 32 (5) ◽  
pp. 490-496 ◽  
Author(s):  
Julianne L. Holleran ◽  
Julien Fourcade ◽  
Merrill J. Egorin ◽  
Julie L. Eiseman ◽  
Robert A. Parise ◽  
...  
Keyword(s):  
Kinase Inhibitor ◽  
Carbonyl Reductase ◽  
In Vitro Metabolism ◽  
Phosphatidylinositol 3 Kinase ◽  
Phosphatidylinositol 3

In vitro metabolism study of the bioactive lignan (-)-Grandisin

Planta Medica ◽  
2012 ◽  
Vol 78 (11) ◽  
Author(s):  
GB Messiano ◽  
RA da S Santos ◽  
LS Ferreira ◽  
RA Simões ◽  
MJ Kato ◽  
...  
Keyword(s):  
In Vitro Metabolism ◽  
Metabolism Study

In vitro metabolism study of the promising anticancer agent the lignan (−)-grandisin

2013 ◽  
Vol 72 ◽  
pp. 240-244 ◽  
Author(s):  
Gisele Baraldi Messiano ◽  
Renan Augusto da Silva Santos ◽  
Leandro De Santis Ferreira ◽  
Rodrigo Almeida Simões ◽  
Valquíria Aparecida Polisel Jabor ◽  
...  
Keyword(s):  
Anticancer Agent ◽  
In Vitro Metabolism ◽  
Metabolism Study
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