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.

Synthesis, in silico, in vitro, and in vivo investigation of 5-[11C]methoxy-substituted sunitinib, a tyrosine kinase inhibitor of VEGFR-2

2012 ◽  
Vol 58 ◽  
pp. 272-280 ◽  
Author(s):  
Julio Caballero ◽  
Camila Muñoz ◽  
Jans H. Alzate-Morales ◽  
Susana Cunha ◽  
Lurdes Gano ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitor ◽  
In Silico ◽  
Kinase Inhibitor

scholarly journals In Vitro and In Silico Analyses of the Inhibition of Human Aldehyde Oxidase by Bazedoxifene, Lasofoxifene, and Structural Analogues

2019 ◽  
Vol 371 (1) ◽  
pp. 75-86 ◽  
Author(s):  
Shiyan Chen ◽  
Karl Austin-Muttitt ◽  
Linghua Harris Zhang ◽  
Jonathan G. L. Mullins ◽  
Aik Jiang Lau
Keyword(s):  
In Silico ◽  
Aldehyde Oxidase ◽  
Structural Analogues ◽  
In Silico Analyses

scholarly journals Tyrosine Kinase Inhibitor Family of Drugs as Prospective Targeted Therapy for COVID-19 Based on In Silico And 3D-Human Vascular Lung Model Studies

2021 ◽  
Author(s):  
Shalini Saxena ◽  
Kranti Meher ◽  
Madhuri Rotella ◽  
Subhramanyam Vangala ◽  
Satish Chandran ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Kinases ◽  
In Silico ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Lung Model ◽  
Common Mechanism ◽  
Model Studies ◽  
Chemical Structures

COVID-19 pandemic has ravaged the world and vaccines have been rapidly developed as preventive measures. But there is no target-based therapy which can be used if infection sets in. Remdesiver and dexamethasone were not designed to combat COVID-19 but are used clinically till better targeted therapies are available. Given this situation target based therapies that intervene in the disease pathway are urgently needed. Since COVID-19 genesis is driven by uncontrolled inflammation and thrombosis and protein kinases are critical in mounting this response, we explored if available tyrosine kinase inhibitors (TKI) can be used as intervention. We profiled four TKI namely Lapatinib, Dasatinib, Pazopanib and Sitravatinib which inhibit tyrosine kinases but are completely distinct in their chemical structures. We demonstrate using in silico and an in vitro 3D-human vascular lung model which profiles anti-inflammatory and anti-thrombogenic properties that all four TKI are active in varying degrees. Our findings that chemically different TKI which share kinase inhibition as the common mechanism of action are active, strongly indicates that it is a tyrosine kinase target-based activity and not off-target arbitrary effect. We propose that TKI, approved for human use and widely available, can be rapidly deployed as specific target-based therapy for COVID-19.

scholarly journals The novel ORFV protein ORFV113 activates LPA-p38 signaling

2021 ◽  
Vol 17 (10) ◽  
pp. e1009971
Author(s):  
Sushil Khatiwada ◽  
Gustavo Delhon ◽  
Sabal Chaulagain ◽  
Daniel L. Rock
Keyword(s):  
Kinase Inhibitor ◽  
Cellular Functions ◽  
P38 Kinase ◽  
Wide Range ◽  
Viral Plaque ◽  
Infected Cells ◽  
Kinase Phosphorylation ◽  
In Cells

Viruses have evolved mechanisms to subvert critical cellular signaling pathways that regulate a wide range of cellular functions, including cell differentiation, proliferation and chemotaxis, and innate immune responses. Here, we describe a novel ORFV protein, ORFV113, that interacts with the G protein-coupled receptor Lysophosphatidic acid receptor 1 (LPA1). Consistent with its interaction with LPA1, ORFV113 enhances p38 kinase phosphorylation in ORFV infected cells in vitro and in vivo, and in cells transiently expressing ORFV113 or treated with soluble ORFV113. Infection of cells with virus lacking ORFV113 (OV-IA82Δ113) significantly decreased p38 phosphorylation and viral plaque size. Infection of cells with ORFV in the presence of a p38 kinase inhibitor markedly diminished ORFV replication, highlighting importance of p38 signaling during ORFV infection. ORFV113 enhancement of p38 activation was prevented in cells in which LPA1 expression was knocked down and in cells treated with LPA1 inhibitor. Infection of sheep with OV-IA82Δ113 led to a strikingly attenuated disease phenotype, indicating that ORFV113 is a major virulence determinant in the natural host. Notably, ORFV113 represents the first viral protein that modulates p38 signaling via interaction with LPA1 receptor.

scholarly journals Correction to: Effects of Phenothiazines on Aldehyde Oxidase Activity Towards Aldehydes and N-Heterocycles: an In Vitro and In Silico Study

2019 ◽  
Vol 44 (2) ◽  
pp. 287-287
Author(s):  
Farnaz Deris-Abdolahpour ◽  
Lida Abdolalipouran-Sadegh ◽  
Siavoush Dastmalchi ◽  
Maryam Hamzeh-Mivehroud ◽  
Omid Zarei ◽  
...  
Keyword(s):  
In Silico ◽  
Oxidase Activity ◽  
Aldehyde Oxidase ◽  
In Silico Study
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