Bioactive Phytoconstituents as Potent Inhibitors of Tyrosine-Protein Kinase Yes (YES1): Implications in Anticancer Therapeutics

Yang, Chunmin; Alam, Afsar; Alhumaydhi, Fahad A.; Khan, Mohd Shahnawaz; Alsagaby, Suliman A.; Abdulmonem, Waleed Al; Hassan, Md. Imtaiyaz; Shamsi, Anas; Bano, Bilqees; Yadav, Dharmendra Kumar

doi:10.3390/molecules27103060

Cited by 13 publications

(9 citation statements)

References 34 publications

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“…A molecular docking study was performed to obtain insights into the structural basis of taurine interactions with CDK6. , The atomic coordinates of CDK6 were taken from the RCSB Protein Data Bank (PDB ID: 6OQO), and heteroatoms, including co-crystallized water molecules, were removed through SwissPDB-Viewer and the MGL AutoDock tools . The three-dimensional structure of taurine was retrieved from the PubChem database (PubChem ID: 1123).…”

Section: Methodsmentioning

confidence: 99%

Inhibiting Cyclin-Dependent Kinase 6 by Taurine: Implications in Anticancer Therapeutics

et al. 2022

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Cyclin-dependent kinase 6 (CDK6) is linked with a cyclin partner and plays a crucial role in the early stages of cancer development. It is currently a potential drug target for developing therapeutic molecules targeting cancer therapy. Here, we have identified taurine as an inhibitor of CDK6 using combined in silico and experimental studies. We performed various experiments to find the binding affinity of taurine with CDK6. Molecular docking analysis revealed critical residues of CDK6 that are involved in taurine binding. Fluorescence measurement studies showed that taurine binds to CDK6 with a significant binding affinity, with a binding constant of K = 0.7 × 10 7 M –1 for the CDK6–taurine complex. Enzyme inhibition assay suggested taurine as a good inhibitor of CDK6 possessing an IC 50 value of 4.44 μM. Isothermal titration calorimetry analysis further confirmed a spontaneous binding of taurine with CDK6 and delineated the thermodynamic parameters for the CDK6–taurine system. Altogether, this study established taurine as a CDK6 inhibitor, providing a base for using taurine and its derivatives in CDK6-associated cancer and other diseases.

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Section: Methodsmentioning

confidence: 99%

Inhibiting Cyclin-Dependent Kinase 6 by Taurine: Implications in Anticancer Therapeutics

et al. 2022

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“…Overexpression of MARK4 enhanced the phosphorylation of NF‐κB by increasing the phosphorylation of IKKα to the total IKKα protein. In the treatment of PDTC, a known inhibitor of the NF‐κB, MARK4 was observed to increase the action of phosphorylated IKKα 40,45,52 . It induces oxidative stress and inflammation by binding to PPARγ and stimulating the NF‐κB pathway in mice adipocytes 59,86 .…”

Section: Introductionmentioning

confidence: 99%

“…Several small molecules were discovered from natural sources to treat multiple diseases 45‐48 . NPs contribute considerably to new therapeutic opportunities, particularly as antitumor and antihypertensive remedies 25,49‐52 . Since MARK4 is considered an attractive drug target for various diseases, new findings on developing potential MARK4 inhibitors are reported continuously.…”

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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“…Several studies have explored the use of AlphaFold protein structure for drug discovery [3][4][5] . A few recent studies evaluated the performance of AlphaFold protein (which was not certified by peer review) is the author/funder.…”

Section: Introductionmentioning

confidence: 99%

“…Several studies have explored the use of AlphaFold protein structure for drug discovery [4][5][6] . At present, only a few recent studies assess the performance of AlphaFold protein structure in VS (virtual screening).…”

Section: Introductionmentioning

confidence: 99%

Assessment of AlphaFold structures and optimization methods for virtual screening

Peng

Lin

et al. 2023

Preprint

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Recent advancements in artificial intelligence such as AlphaFold, have enabled more accurate prediction of protein three-dimensional structure from amino acid sequences. This has attracted significant attention, especially for the application of AlphaFold in drug discovery. Moreover, how to take full advantage of AlphaFold to assist with virtual screening remains elusive. We comprehensively evaluated the AlphaFold structures of 51 selected targets from the DUD-E database in virtual screening. Our analyses show that the virtual screening performance of about 35% of the AlphaFold structures was equivalent to that of DUD-E structures, and about 25% of the AlphaFold structures yielded better results than the DUD-E structures. Remarkably, for the 23 targets, AlphaFold structures produced slightly better results than the Apo structures. Moreover, we developed a new consensus scoring method based on Z-score standardization and exponential function, which showed improved screening performance compared to traditional scoring methods. By implementing a multi-stage virtual screening process and the new consensus scoring method, we were able to improve the speed of virtual screening by about nine times without compromising the enrichment factor. Overall, our results provide insights into the potential use of AlphaFold in drug discovery and highlight the value of consensus scoring and multi-stage virtual screening.

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Bioactive Phytoconstituents as Potent Inhibitors of Tyrosine-Protein Kinase Yes (YES1): Implications in Anticancer Therapeutics

Cited by 13 publications

References 34 publications

Inhibiting Cyclin-Dependent Kinase 6 by Taurine: Implications in Anticancer Therapeutics

Inhibiting Cyclin-Dependent Kinase 6 by Taurine: Implications in Anticancer Therapeutics

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

Assessment of AlphaFold structures and optimization methods for virtual screening

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