Inhibition of PDK3 by artemisinin, a repurposed antimalarial drug in cancer therapy

Anwar, Saleha; DasGupta, Debarati; Azum, Naved; Alfaifi, Sulaiman Y. M.; Asiri, Abdullah M.; Alhumaydhi, Fahad A.; Alsagaby, Suliman A.; Sharaf, Sharaf E; Shahwan, Moyad; Hassan, Md. Imtaiyaz

doi:10.1016/j.molliq.2022.118928

Cited by 18 publications

(18 citation statements)

References 87 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The docking was performed using InstaDock [ 28 ] where search space was defined as −39.46, −14.339, and −1.963 with sizes 50, 70, and 80 for X, Y, and Z coordinates, respectively. All other conditions and parameters were followed as per earlier published literature [ 29 , 30 ].…”

Section: Methodsmentioning

confidence: 99%

“…To obtain the parameters of the ligand (Mtf), we performed the geometry optimization of the fragment using the B3LYP/6-31G(d) method in the Gaussian 16 program [ 31 ]. All other conditions and parameters were followed as per earlier published literature [ 29 , 30 ].…”

Section: Methodsmentioning

confidence: 99%

“…A five step equilibration was set up, gradually dialling down the harmonic restraints on the protein backbone from 5, 2, 1, 0.1 kcal/mol Å 2 ; at last step there was no limitation. All other conditions and parameters were followed as per earlier published literature [ 29 , 30 ].…”

Section: Methodsmentioning

confidence: 99%

See 2 more Smart Citations

Inhibition of Microtubule Affinity Regulating Kinase 4 by Metformin: Exploring the Neuroprotective Potential of Antidiabetic Drug through Spectroscopic and Computational Approaches

et al. 2022

Self Cite

View full text Add to dashboard Cite

Microtubule affinity regulating kinase 4 (MARK4) regulates the mechanism of microtubules by its ability to phosphorylate the microtubule-associated proteins (MAP’s). MARK4 is known for its major role in tau phosphorylation via phosphorylating Ser262 residue in the KXGS motif, which results in the detachment of tau from microtubule. In lieu of this vital role in tau pathology, a hallmark of Alzheimer’s disease (AD), MARK4 is a druggable target to treat AD and other neurodegenerative disorders (NDs). There is growing evidence that NDs and diabetes are connected with many pieces of literature demonstrating a high risk of developing AD in diabetic patients. Metformin (Mtf) has been a drug in use against type 2 diabetes mellitus (T2DM) for a long time; however, recent studies have established its therapeutic effect in neurodegenerative diseases (NDs), namely AD, Parkinson’s disease (PD) and amnestic mild cognitive impairment. In this study, we have explored the MARK4 inhibitory potential of Mtf, employing in silico and in vitro approaches. Molecular docking demonstrated that Mtf binds to MARK4 with a significant affinity of −6.9 kcal/mol forming interactions with binding pocket’s critical residues. Additionally, molecular dynamics (MD) simulation provided an atomistic insight into the binding of Mtf with MARK4. ATPase assay of MARK4 in the presence of Mtf shows that it inhibits MARK4 with an IC50 = 7.05 µM. The results of the fluorescence binding assay demonstrated significant binding of MARK4 with a binding constant of 0.6 × 106 M−1. The present study provides an additional axis towards the utilization of Mtf as MARK4 inhibitor targeting diabetes with NDs.

show abstract

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Inhibition of Microtubule Affinity Regulating Kinase 4 by Metformin: Exploring the Neuroprotective Potential of Antidiabetic Drug through Spectroscopic and Computational Approaches

et al. 2022

Self Cite

View full text Add to dashboard Cite

show abstract

“…Post a quick minimization using steepest descent and Conjugate gradient methods, temperature ramping steps were performed, followed by a slow timed elaborate equilibration followed. All further steps were followed as has been mentioned in previous reports 78–81 …”

Section: Methodsmentioning

confidence: 99%

Investigating binding mechanism of thymoquinone to human transferrin, targeting Alzheimer's disease therapy

Xue

DasGupta

Alam

et al. 2022

J of Cellular Biochemistry

Self Cite

View full text Add to dashboard Cite

Iron deposition in the central nervous system (CNS) is one of the causes of neurodegenerative diseases. Human transferrin (hTf) acts as an iron carrier present in the blood plasma, preventing it from contributing to redox reactions. Plant compounds and their derivatives are frequently being used in preventing or delaying Alzheimer's disease (AD). Thymoquinone (TQ), a natural product has gained popularity because of its broad therapeutic applications. TQ is one of the significant phytoconstituent of Nigella sativa. The binding of TQ to hTf was determined by spectroscopic methods and isothermal titration calorimetry. We have observed that TQ strongly binds to hTf with a binding constant (K) of 0.22 × 106 M−1 and forming a stable complex. In addition, isothermal titration calorimetry revealed the spontaneous binding of TQ with hTf. Molecular docking analysis showed key residues of the hTf that were involved in the binding to TQ. We further performed a 250 ns molecular dynamics simulation which deciphered the dynamics and stability of the hTf‐TQ complex. Structure analysis suggested that the binding of TQ doesn't cause any significant alterations in the hTf structure during the course of simulation and a stable complex is formed. Altogether, we have elucidated the mechanism of binding of TQ with hTf, which can be further implicated in the development of a novel strategy for AD therapy.

show abstract

“…Natural products are extensively used to target cancer therapy with minimal side effects ( Anwar et al, 2020a ; Anwar et al, 2020b ; Anjum et al, 2021 ; Anwar et al, 2021 ; Anwar et al, 2022a ; Anwar et al, 2022b ; Anwar et al, 2022c ). Cinnamomum zeylanicum (CZ) is a tropical evergreen plant belonging to the genus Cinnamomum.…”

Section: Introductionmentioning

confidence: 99%

Cinnamomum zeylanicum Extract and its Bioactive Component Cinnamaldehyde Show Anti-Tumor Effects via Inhibition of Multiple Cellular Pathways

et al. 2022

Self Cite

View full text Add to dashboard Cite

Cinnamomum zeylanicum is a tropical plant with traditional medicinal significance that possesses antimicrobial, antifungal, anti-parasitic, and anti-tumor properties. Here, we have elucidated the anti-tumor effects of Cinnamomum zeylanicum extract (CZE) and its bioactive compound cinnamaldehyde (CIN) on oral cancer and elucidated underlying molecular mechanisms. Anti-tumor activities of CZE and CIN were demonstrated by various in vitro experiments on oral cancer cells (SCC-4, SCC-9, SCC-25). The cell proliferation, growth, cell cycle arrest, apoptosis, and autophagy were analyzed by MTT, clonogenic assay, propidium iodide, annexin-V-PI, DAPI, and acridine orange staining, respectively. The binding affinity of CIN towards dihydrofolate reductase and p38-MAP kinase alpha was analyzed by molecular docking. Western blot assay was performed to assess the alteration in the expression of various proteins. CZE and CIN treatment significantly inhibited the growth and proliferation of oral cancer cells in a dose-dependent manner. These treatments further induced apoptosis, cell cycle arrest, and autophagy. CZE and CIN inhibited the invasion and cytoplasmic translocation of NF-κB in these cell lines. CIN showed a high affinity to MAP kinase P38 alpha and dihydrofolate reductase with binding affinities of −6.8 and −5.9 kcal/mol, respectively. The cancer cells showed a decreased expression of various PI3k-AKT-mTOR pathways related to VEGF, COX-2, Bcl-2, NF-κB, and proteins post-treatment.

show abstract

Inhibition of PDK3 by artemisinin, a repurposed antimalarial drug in cancer therapy

Cited by 18 publications

References 87 publications

Inhibition of Microtubule Affinity Regulating Kinase 4 by Metformin: Exploring the Neuroprotective Potential of Antidiabetic Drug through Spectroscopic and Computational Approaches

Inhibition of Microtubule Affinity Regulating Kinase 4 by Metformin: Exploring the Neuroprotective Potential of Antidiabetic Drug through Spectroscopic and Computational Approaches

Investigating binding mechanism of thymoquinone to human transferrin, targeting Alzheimer's disease therapy

Cinnamomum zeylanicum Extract and its Bioactive Component Cinnamaldehyde Show Anti-Tumor Effects via Inhibition of Multiple Cellular Pathways

Contact Info

Product

Resources

About