Bioactive phytoconstituents as potent inhibitors of casein kinase-2: dual implications in cancer and COVID-19 therapeutics

Anjum, Farah; Sulaimani, Md Nayab; Shafie, Alaa; Ashraf, Ghulam Md; Bilgrami, Anwar L.; Alhumaydhi, Fahad A.; Alsagaby, Suliman A.; Yadav, Dharmendra Kumar; Hassan, Md. Imtaiyaz

doi:10.1039/d1ra09339h

Cited by 22 publications

(5 citation statements)

References 66 publications

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“…The GROMACS tools were used to investigate the protein-ligand stability from the resulting trajectories. The generated outputs were analyzed for RMSF, RMSD, Rg, H-bonds, SASA, distance cross-correlation matrix, secondary structure analysis, and PCA [48][49][50][51].…”

Section: Simulationmentioning

confidence: 99%

Identification of Potential Bioactive Phytochemicals for the Inhibition of Platelet-Derived Growth Factor Receptor β: An integrated docking and MD simulation approach

Habib,

Sulaimani,

Hussain

et al. 2024

Preprint

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Platelet-derived growth factor receptor beta (PDGFRβ) belongs to the receptor tyrosine kinase (RTK) protein family and is implicated in various diseases, including cancer. Its signaling pathway has been linked to various human meningioma and atherosclerosis. Due to its pivotal role in disease pathogenesis, PDGFRβ has emerged as a promising drug target in cancer therapy and the treatment of other disorders. This study aimed to identify potential PDGFRβ inhibitors through virtual screening of phytochemicals extracted from the IMPPAT database. The initial assessment involved applying the Lipinski rule-of-five to evaluate the physicochemical properties of the molecules. Subsequently, a comprehensive analysis encompassing binding affinity assessment, PAINS filter application, ADMET profiling, and PASS prediction was conducted. Among the screened compounds, Genostrychnine and Chelidonine exhibited remarkable affinity and specificity in their interactions with the PDGFRβ kinase domain. To gain insights into the temporal evolution and dynamics of these interactions, all-atom molecular dynamics (MD) simulations and essential dynamics analysis were employed. These computational techniques provided valuable insights into the behavior and stability of the PDGFRβ-ligand complexes over time. Based on our findings, we propose that Genostrychnine and Chelidonine merit further investigation through in vivo and in vitro studies to evaluate their potential for managing PDGFRβ-associated malignancies. In conclusion, this study underscores the potential of Genostrychnine and Chelidonine as promising PDGFRβ inhibitors. Further experimental investigations are required to validate their efficacy and assess their therapeutic potential for PDGFRβ-related diseases, with a particular focus on cancer management.

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Section: Simulationmentioning

confidence: 99%

Identification of Potential Bioactive Phytochemicals for the Inhibition of Platelet-Derived Growth Factor Receptor β: An integrated docking and MD simulation approach

Habib,

Sulaimani,

Hussain

et al. 2024

Preprint

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“…27 1.9 | MARK4 inhibitors Kinases are the most important proteins that control many cellular functions via phosphorylation. [118][119][120][121][122] Subsequently, modification in the kinase role or action in pathological states makes kinases essential targets for drug discovery and development. 70,123 The present anti-MARK4 drug discovery and improvement approaches combine computational tools and experimentally examine the potential inhibitors of MARK4.…”

Section: Therapeutic Implication Of Mark4 In Alzheimer's Diseasementioning

confidence: 99%

“…Kinases are the most important proteins that control many cellular functions via phosphorylation 118–122 . Subsequently, modification in the kinase role or action in pathological states makes kinases essential targets for drug discovery and development 70,123 .…”

Section: Introductionmentioning

confidence: 99%

Therapeutic targeting of microtubule affinity‐regulating kinase 4 in cancer and neurodegenerative diseases

Alam,

Ahmed,

Abid

et al. 2023

J of Cellular Biochemistry

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Microtubule affinity‐regulating kinase 4 (MARK4) is a member of the Ser/Thr protein kinase family, phosphorylates the microtubule‐connected proteins and plays a vital role in causing cancers and neurodegenerative diseases. This kinase modulates multiple signaling pathways, including mammalian target of rapamycin, nuclear factor‐κB, and Hippo‐signaling, presumably responsible for cancer and Alzheimer's. MARK4 acts as a negative controller of the Hippo‐kinase cassette for promoting YAP/TAZ action, and the loss of MARK4 detains the tumorigenic properties of cancer cells. MARK4 is involved in tau hyperphosphorylation that consequently affects neurodegeneration. MARK4 is a promising drug target for cancer, diabetes, and Alzheimer's. Developing the potent and selective inhibitors of MAKR4 are promising in the therapeutic management of associated diseases. Despite its great significance, a few reviews are available to discuss its structure, function and clinical significance. In the current review, we aimed to provide detailed information on the structural features of MARK4 targeted in drug development and its role in various signaling pathways related to cancer and neurodegenerative diseases. We further described the therapeutic potential of MARK4 inhibitors in preventing numerous diseases. Finally, the updated information on MARK4 will be helpful in the further development of effective therapeutic molecules.

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“…Their structural diversity and ability to interact with multiple targets make phytoconstituents attractive candidates for drug discovery and development 11 . The research motivation lies in the potential of phytoconstituents that have offered innovative solutions in drug discovery 10,12–15 …”

Section: Introductionmentioning

confidence: 99%

“…11 The research motivation lies in the potential of phytoconstituents that have offered innovative solutions in drug discovery. 10,[12][13][14][15] In recent years, computational methods have emerged as powerful tools in the initial stages of drug discovery, allowing for the efficient screening of large compound libraries. [16][17][18] Virtual screening, which involves computer-based docking simulations, enables the identification of potential drug candidates by predicting their binding affinities to target proteins.…”

mentioning

confidence: 99%

An integrated docking and molecular dynamics simulation approach to discover potential inhibitors of activin receptor‐like kinase 1

Jairajpuri,

Mohammad,

Hussain

et al. 2023

J of Molecular Recognition

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Activin receptor‐like kinase 1 (ALK1) is a transmembrane receptor involved in crucial signaling pathways associated with angiogenesis and vascular development. Inhibition of ALK1 signaling has emerged as a promising therapeutic strategy for various angiogenesis‐related diseases, including cancer and hereditary hemorrhagic telangiectasia. This study aimed to investigate the potential of phytoconstituents as inhibitors of ALK1 using a combined approach of virtual screening and molecular dynamics (MDs) simulations. Phytoconstituents from the IMPPAT 2.0 database underwent virtual screening to identify potential inhibitors of ALK1. The compounds were initially filtered based on physicochemical parameters, following Lipinski's rules and the PAINS filter. Subsequently, compounds demonstrating high binding affinities in docking analysis were further analyzed. Additional assessments, including ADMET, PAINS, and PASS evaluations, were conducted to identify more potent hits. Through interaction analysis, a phytoconstituent, Candidine, exhibited appreciable affinity and specific interactions with the ALK1 active site. To validate the results, MD simulations and principal components analysis were performed. The MD simulations demonstrated that Candidine stabilized the ALK1 structure and reduced conformational fluctuations. In conclusion, Candidine shows promising potential as binding partners of ALK1. These findings provide a foundation for further exploration and development of Candidine as a lead molecule for therapeutic interventions targeting ALK1‐associated diseases.

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Bioactive phytoconstituents as potent inhibitors of casein kinase-2: dual implications in cancer and COVID-19 therapeutics

Abstract: Showing protein–ligands interactions, electrostatic potential of CK2 bound to selected compounds, free energy landscapes of CK2-stylopine, and CK2-dehydroevodiamines complexes.

Cited by 22 publications

References 66 publications

Identification of Potential Bioactive Phytochemicals for the Inhibition of Platelet-Derived Growth Factor Receptor β: An integrated docking and MD simulation approach

Identification of Potential Bioactive Phytochemicals for the Inhibition of Platelet-Derived Growth Factor Receptor β: An integrated docking and MD simulation approach

Therapeutic targeting of microtubule affinity‐regulating kinase 4 in cancer and neurodegenerative diseases

An integrated docking and molecular dynamics simulation approach to discover potential inhibitors of activin receptor‐like kinase 1

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