3D-QSAR, docking, molecular dynamics simulation and free energy calculation studies of some pyrimidine derivatives as novel JAK3 inhibitors

Balupuri, Anand; Balasubramanian, Pavithra K.; Cho, Seung Joo

doi:10.1016/j.arabjc.2017.09.009

Cited by 40 publications

(13 citation statements)

References 65 publications

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“…The sequence and structure of the kinase domains of the four members of JAK family are highly similar; however, they are still slightly different in the amino acids nearby the inhibitor binding sites. Certain studies have shown that the covalent binding between JAK3 Cys909 and inhibitor may be an excellent attempt . It also provides direction for the structural modification of CE for the improvement of its binding ability with JAK3 protein in the future.…”

Section: Discussionmentioning

confidence: 99%

“…Certain studies have shown that the covalent binding between JAK3 Cys909 and inhibitor may be an excellent attempt. 65 It also provides direction for the structural modification of CE for the improvement of its binding ability with JAK3 protein in the future. Pharmacokinetics is the digital representation of the changes of drugs after entering the human body, which can provide guidance for the use of drugs.…”

Section: ■ Discussionmentioning

confidence: 99%

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Cedrol from Ginger Ameliorates Rheumatoid Arthritis via Reducing Inflammation and Selectively Inhibiting JAK3 Phosphorylation

Zhang

Shen

Zhao³

et al. 2021

J. Agric. Food Chem.

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Ginger, as a food spice, is widely applied due to its extensive effects. Cedrol (CE) found in ginger is a sesquiterpene with anti-inflammatory activity. The objective of this research is to discuss the efficacy of CE on ameliorating rheumatoid arthritis (RA). CE inhibited chronic inflammation and pain in a dose-dependent manner accompanied by rapid onset and long duration. Besides, CE treatment effectively ameliorated the paw edema volume and arthritis score with no significant effect on body weight. Organ index, T-cell and B-cell proliferation, histopathology, and immunohistochemistry demonstrated that CE had immunological enhancement and attenuated RA effects. Remarkably, inhibition of phosphorylated-JAK3 protein, thereby abating the secretion of pro-inflammatory cytokines and inflammation-related mediators, was involved in the potential mechanism of CE efficiency through forming a hydrogen bond with ARG953 and ILE955 in the JAK3 active pocket. At the same time, the pharmacokinetic results showed that the absolute bioavailability of CE at 20, 40, and 80 mg/kg was 30.30, 23.68, and 16.11%, respectively. The current results offered clues for mastering the ameliorated RA of CE and further perfected the effective substance basis on the antiinflammatory effect of ginger, which was beneficial for further applications.

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Section: Discussionmentioning

confidence: 99%

Section: ■ Discussionmentioning

confidence: 99%

Cedrol from Ginger Ameliorates Rheumatoid Arthritis via Reducing Inflammation and Selectively Inhibiting JAK3 Phosphorylation

Zhang

Shen

Zhao³

et al. 2021

J. Agric. Food Chem.

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“…2. It can be concluded that the model presents relatively high predictive power, as the model satis ed the external and internal validation criteria: R 2 > 0.6, Q 2 LMO and Q 2 LOO > 0.5, CCC > 0.85, Q 2 F1 , Q 2 F2 and Q 2 F3 > 0.6, r 2 m > 0.5, △r 2 m < 0.2 and 0.85 ≤ k ≤ 1.15 or 0.85 ≤ k′ ≤ 1.15 (Balupuri et al 2020). The difference between R 2 and Q 2 LOO is 0.11 units, less than 0.2, indicating the absence of over ting (Kiralj and Ferreira 2009).…”

Section: D-qsar Modelmentioning

confidence: 99%

4D-QSAR Analyses for EGFR Inhibitors Based on CDDA-OPS-GA Method

Qin

Zeng²,

Zhao

et al. 2021

Preprint

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Epidermal growth factor receptor is a preferred target for treating cancer. Compared to 3D-QSAR, 4D-QSAR has the feature of conformational flexibility and free alignment for individual ligands. In present studies, the 4D-QSAR of 131 analogs of 4-anilino quinazoline for EGFR inhibitors was built. The GROMACS package was employed to yield the conformational ensemble profile. The field descriptors of Coulomb and Lennard−Jones potentials were calculated by LQTA-QSAR. The filter descriptors and variable selection is very important, which was performed by means of comparative distribution detection algorithm (CDDA), ordered predictors selection (OPS) and genetic algorithm (GA) method. Best 4D-QSAR model yielded satisfactory statistics (R2 = 0.71), good performance in internal (Q2LOO = 0.60) and external prediction (R2pred = 0.69, k = 0.97, k′ = 1.01). The 4D-QSAR was shown to be robust (Q2LMO = 0.59) and was not built by chance (R2YS = 0.17, Q2YS = −0.25). The model has a good potential for rational design new EGFR inhibitors.

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“…The calculation process using the MM-GBSA method provided some information about the complete energy components in the gas state (eqn (18)) and the solvation state (eqn (19)). The candidates that gave good results were evaluated by comparing them with the binding free energy of the native ligand as a benchmark for the criterion of DG candidate ligand < DG native ligand.…”

Section: Molecular Docking and Molecular Dynamic Simulationmentioning

confidence: 99%

“…[14][15][16][17] Several computational chemistry techniques developed for drug design, such as Molecular Docking (MD) and Molecular Dynamic Simulation (MDS), using in silico approaches have shown very good accuracy in studying interactions between drugs and protein targets. 18,19 Molecular docking has shown good performance in studying the initial coordinates of drug interactions (ligands) with protein targets (receptor). 20 Additionally, molecular dynamic simulation can predict the free energy of ligand-receptor binding by using the Molecular Mechanics-Generalized Born Surface Area (MM-GBSA) method that has been widely used.…”

Section: Introductionmentioning

confidence: 99%

In silicoapproach: biological prediction of nordentatin derivatives as anticancer agent inhibitors in the cAMP pathway

et al. 2020

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3D-QSAR, docking, molecular dynamics simulation and free energy calculation studies of some pyrimidine derivatives as novel JAK3 inhibitors

Cited by 40 publications

References 65 publications

Cedrol from Ginger Ameliorates Rheumatoid Arthritis via Reducing Inflammation and Selectively Inhibiting JAK3 Phosphorylation

Cedrol from Ginger Ameliorates Rheumatoid Arthritis via Reducing Inflammation and Selectively Inhibiting JAK3 Phosphorylation

4D-QSAR Analyses for EGFR Inhibitors Based on CDDA-OPS-GA Method

In silicoapproach: biological prediction of nordentatin derivatives as anticancer agent inhibitors in the cAMP pathway

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