Insights into the Binding Recognition and Susceptibility of Tofacitinib toward Janus Kinases

Sanachai, Kamonpan; Mahalapbutr, Panupong; Choowongkomon, Kiattawee; Poo-arporn, Rungtiva P.; Wolschann, Peter; Rungrotmongkol, Thanyada

doi:10.1021/acsomega.9b02800

Cited by 49 publications

(54 citation statements)

References 63 publications

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“…Ruxolitinib is a JAK1/2 inhibitor, as DN pathogenesis involves JAK2 [ 45 ]. Notably, various JAK inhibitors vary in their binding affinity, e.g., tofacitinib has a higher binding affinity to JAK3 compared to JAK1/2 [ 46 ].…”

Section: Discussionmentioning

confidence: 99%

Early Renoprotective Effect of Ruxolitinib in a Rat Model of Diabetic Nephropathy

et al. 2021

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Diabetic kidney disease (DKD) is still one of the unresolved major complications of diabetes mellitus, which leads ultimately to end-stage renal disease in both type 1 and type 2 diabetes patients. Available drugs that suppress the renin–angiotensin system have partially minimized the disease impact. Yet, there is an unmet need for new therapeutic interventions to protect the kidneys of diabetic patients. In DN, glomerular sclerosis and tubulointerstitial fibrosis are mediated through several pathways, of which JAK/STAT is a key one. The current study explored the potential renoprotective effect of the JAK1/JAK2 inhibitor ruxolitinib (at doses of 0.44, 2.2, and 4.4 mg·kg−1) compared to that of enalapril at a dose of 10 mg·kg−1, in a rat model of streptozotocin-induced diabetes mellitus over 8 weeks. The effect of ruxolitinib was assessed by determining urinary albumin/creatinine ratio, serum level of cystatin, and levels of TGF-β1, NF-κB, and TNF-α in renal tissue homogenates by biochemical assays, the glomerular sclerosis and tubulointerstitial fibrosis scores by histological analysis, and fibronectin, TGF-β1, and Vimentin levels by immunohistochemical staining with the respective antibodies. Our results revealed a significant early favorable effect of a two-week ruxolitinib treatment on the renal function, supported by a decline in the proinflammatory biomarkers of DKD. This pre-clinical study suggests that the renoprotective effect of ruxolitinib in the long term should be investigated in animals, as this drug may prove to be a potential option for the treatment of diabetic kidney disease.

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Section: Discussionmentioning

confidence: 99%

Early Renoprotective Effect of Ruxolitinib in a Rat Model of Diabetic Nephropathy

et al. 2021

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“…Note that the vinyl sulfone derivatives were constructed according to their availability from previous study [ 21 , 22 , 23 , 24 ]. All the ligands were optimized using the Gaussian 09 program (HF/6–31d) as per the standard protocol [ 42 , 43 , 44 ]. The protonation state of all studied ligands was characterized using the ChemAxon [ 45 ].…”

Section: Methodsmentioning

confidence: 99%

“…The starting crystal structure of EGFR-TK (PDB ID: 1M17) [ 39 ] was obtained from Protein Data Bank (PDB). The 3D structure of vinyl sulfone derivatives and known drug inhibitor (EGFR-TK) of EGFR-TK were generated and optimized HF/6–31G(d) method implemented in the Gaussian09 software [ 42 , 43 , 44 ]. The protein-ligand complexes were generated using the CDOCKER module accordance the standard protocol [ 50 ].…”

Section: Methodsmentioning

confidence: 99%

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

et al. 2021

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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.

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“…A distance of ≤ 3.5 Å and an angle cut-off of ≥120° were used for hydrogen bond calculations. The same criterion was used in earlier studies (Jeffrey, 1997 ; Hu et al, 2016 ; Shi et al, 2018 ; Sanachai et al, 2020 ).…”

Section: Methodsmentioning

confidence: 99%

Computational Investigation of Structural Dynamics of SARS-CoV-2 Methyltransferase-Stimulatory Factor Heterodimer nsp16/nsp10 Bound to the Cofactor SAM

Jonniya

Roy

et al. 2020

Front. Mol. Biosci.

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Recently, a highly contagious novel coronavirus disease 2019 (COVID-19), caused by SARS-CoV-2, has emerged, posing a global threat to public health. Identifying a potential target and developing vaccines or antiviral drugs is an urgent demand in the absence of approved therapeutic agents. The 5′-capping mechanism of eukaryotic mRNA and some viruses such as coronaviruses (CoVs) are essential for maintaining the RNA stability and protein translation in the virus. SARS-CoV-2 encodes S-adenosyl-L-methionine (SAM) dependent methyltransferase (MTase) enzyme characterized by nsp16 (2′-O-MTase) for generating the capped structure. The present study highlights the binding mechanism of nsp16 and nsp10 to identify the role of nsp10 in MTase activity. Furthermore, we investigated the conformational dynamics and energetics behind the binding of SAM to nsp16 and nsp16/nsp10 heterodimer by employing molecular dynamics simulations in conjunction with the Molecular Mechanics Poisson-Boltzmann Surface Area (MM/PBSA) method. We observed from our simulations that the presence of nsp10 increases the favorable van der Waals and electrostatic interactions between SAM and nsp16. Thus, nsp10 acts as a stimulator for the strong binding of SAM to nsp16. The hydrophobic interactions were predominately identified for the nsp16-nsp10 interactions. Also, the stable hydrogen bonds between Ala83 (nsp16) and Tyr96 (nsp10), and between Gln87 (nsp16) and Leu45 (nsp10) play a vital role in the dimerization of nsp16 and nsp10. Besides, Computational Alanine Scanning (CAS) mutagenesis was performed, which revealed hotspot mutants, namely I40A, V104A, and R86A for the dimer association. Hence, the dimer interface of nsp16/nsp10 could also be a potential target in retarding the 2′-O-MTase activity in SARS-CoV-2. Overall, our study provides a comprehensive understanding of the dynamic and thermodynamic process of binding nsp16 and nsp10 that will contribute to the novel design of peptide inhibitors based on nsp16.

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Insights into the Binding Recognition and Susceptibility of Tofacitinib toward Janus Kinases

Cited by 49 publications

References 63 publications

Early Renoprotective Effect of Ruxolitinib in a Rat Model of Diabetic Nephropathy

Early Renoprotective Effect of Ruxolitinib in a Rat Model of Diabetic Nephropathy

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

Computational Investigation of Structural Dynamics of SARS-CoV-2 Methyltransferase-Stimulatory Factor Heterodimer nsp16/nsp10 Bound to the Cofactor SAM

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