Molecular modeling study of CP-690550 derivatives as JAK3 kinase inhibitors through combined 3D-QSAR, molecular docking, and dynamics simulation techniques

Wang, Jing Li; Li, Cheng; Wang, Tian Chi; Deng, Wei; Wu, Fan

doi:10.1016/j.jmgm.2016.12.020

Cited by 21 publications

(18 citation statements)

References 44 publications

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“…Thus, it has attracted researchers to find efficient tyrosinase inhibitors. Recently, molecular docking for modeling the antityrosinase activity of compounds had been used widely in drug design [ 13 ].…”

Section: Introductionmentioning

confidence: 99%

The antityrosinase and antioxidant activities of flavonoids dominated by the number and location of phenolic hydroxyl groups

et al. 2018

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BackgroundCompounds with the ability to scavenge reactive oxygen species (ROS) and inhibit tyrosinase may be useful for the treatment and prevention from ROS-related diseases. The number and location of phenolic hydroxyl of the flavonoids will significantly influence the inhibition of tyrosinase activity. Phenolic hydroxyl is indispensable to the antioxidant activity of flavonoids. Isoeugenol, shikonin, baicalein, rosmarinic acid, and dihydromyricetin have respectively one, two, three, four, or five phenolic hydroxyls. The different molecular structures with the similar structure to l-3,4-dihydroxyphenylalanine (l-DOPA) were expected to the different antityrosinase and antioxidant activities.MethodsThis investigation tested the antityrosinase activity, the inhibition constant, and inhibition type of isoeugenol, shikonin, baicalein, rosmarinic acid, and dihydromyricetin. Molecular docking was examined by the Discovery Studio 2.5 (CDOCKER Dock, Dassault Systemes BIOVIA, USA). This experiment also examined the antioxidant effects of the five compounds on supercoiled pBR322 plasmid DNA, lipid peroxidation in rat liver mitochondria in vitro, and DPPH, ABTS, hydroxyl, or superoxide free radical scavenging activity in vitro.ResultsThe compounds exhibited good antityrosinase activities. Molecular docking results implied that the compounds could interact with the amino acid residues in the active site center of antityrosinase. These compounds also exhibited antioxidant effects on DPPH, ABTS, hydroxyl, or superoxide free radical scavenging activity in vitro, lipid peroxidation in rat liver mitochondria induced by Fe2+/vitamin C system in vitro, and supercoiled pBR322 plasmid DNA. The activity order is isoeugenol < shikonin < baicalein < rosmarinic acid < dihydromyricetin. The results showed the compounds with more phenolic hydroxyls have more antioxidant and antityrosinase activities.ConclusionThis was the first study of molecular docking for modeling the antityrosinase activity of compounds. This was also the first study of the protective effects of compounds on supercoiled pBR322 plasmid DNA, the lipid peroxidation inhibition activity in liver mitochondria. These results suggest that the compounds exhibited antityrosinase and antioxidant activities may be useful in skin pigmentation and food additives.Electronic supplementary materialThe online version of this article (10.1186/s13020-018-0206-9) contains supplementary material, which is available to authorized users.

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Section: Introductionmentioning

confidence: 99%

The antityrosinase and antioxidant activities of flavonoids dominated by the number and location of phenolic hydroxyl groups

et al. 2018

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“…In previous reports, structure-based computational molecular simulation has been used to identify candidate compounds able to inhibit JAK3 phosphorylation [52, 53]. The JAK3 ATP-binding pocket domain structure was used for computational chemical assays of small molecules.…”

Section: Discussionmentioning

confidence: 99%

Identification of Chinese Herbal Compounds with Potential as JAK3 Inhibitors

Gao

Deng

et al. 2019

Evidence-Based Complementary and Alternative Medicine

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The Janus kinases (JAKs) consist of four similar tyrosine kinases and function as key hubs in the signaling pathways that are implicated in both innate and adaptive immunity. Among the four members, JAK3 is probably the more attractive target for treatment of inflammatory diseases because its inhibition demonstrates the greatest immunosuppression and most profound effect in the treatment of such disorders. Although many JAK3 inhibitors are already available, certain shortcomings have been identified, mostly acquired drug resistance or unwanted side effects. To discover and identify new promising lead candidates, in this study, the structure of JAK3 (3LXK) was obtained from the Protein Data Bank and used for simulation modeling and protein-ligand interaction analysis. The ~36,000 Chinese herbal compounds obtained from TCM Database@Taiwan were virtually screened by AutoDock Vina docking program and filtered with Lipinski’s Rules and ADME/T virtual predictions. Because of high occurrence of fake hits during docking, we selected 12 phytochemicals which have demonstrated modulating JAKs expressions among the top 50 chemicals from docking results. To validate whether these compounds are able to directly mediate JAK3 kinase, we have investigated the inhibitory activity using enzymatic activity assays, western blot, and HEK 293 cell STAT5 transactivity assays. The molecular analysis included docking and molecular dynamics (MD) simulations in order to investigate structural conformations and to explore the key amino acids in the interaction between JAK3 kinase and its putative ligands. The results demonstrated that Cryptotanshinone, Icaritin, and Indirubin exhibited substantial inhibitory activity against JAK3 kinase in vitro. The results also provide binding models of the protein-ligand interaction, detailing the interacting amino acid residues at the active ATP-binding domains of JAK3 kinase. In conclusion, our work discovered 3 potential natural inhibitors of JAK3 kinase and could provide new possibilities and stimulate new insights for the treatment of JAK3-targeted diseases.

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“…They found that the PPC binding affinity was closer to the experimental value reported by Nantermet et al ( 2003 ). For immune disorders, studies on Janus kinases (Zhang W. et al, 2016 ; Wang J. L. et al, 2017 ), interleukin 10 cytokine (Ni et al, 2017 ), and receptor-related orphan receptor-gamma-t (Wang F. F. et al, 2015 ), were reported. For inflammatory disorders, targets such as COX-2 (Chaudhary and Aparoy, 2017 ), interleukin 6 (Verma R. et al, 2016 ), toll-like receptors (Shen et al, 2016 ), human leukocyte antigen (Kongkaew et al, 2015 ), chymase enzyme (Verma et al, 2017 ), tumor necrosis factor (Ivanisenko et al, 2014 ), and Nalp3 (Sahoo et al, 2014b ) were studied.…”

Section: Applications Of Mmpbsamentioning

confidence: 99%

Recent Developments and Applications of the MMPBSA Method

Wang

Greene

Xiao

et al. 2018

Front. Mol. Biosci.

471

327

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The Molecular Mechanics Poisson-Boltzmann Surface Area (MMPBSA) approach has been widely applied as an efficient and reliable free energy simulation method to model molecular recognition, such as for protein-ligand binding interactions. In this review, we focus on recent developments and applications of the MMPBSA method. The methodology review covers solvation terms, the entropy term, extensions to membrane proteins and high-speed screening, and new automation toolkits. Recent applications in various important biomedical and chemical fields are also reviewed. We conclude with a few future directions aimed at making MMPBSA a more robust and efficient method.

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Molecular modeling study of CP-690550 derivatives as JAK3 kinase inhibitors through combined 3D-QSAR, molecular docking, and dynamics simulation techniques

Cited by 21 publications

References 44 publications

The antityrosinase and antioxidant activities of flavonoids dominated by the number and location of phenolic hydroxyl groups

The antityrosinase and antioxidant activities of flavonoids dominated by the number and location of phenolic hydroxyl groups

Identification of Chinese Herbal Compounds with Potential as JAK3 Inhibitors

Recent Developments and Applications of the MMPBSA Method

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