Discovery of Hordenine as a Potential Inhibitor of Pyruvate Dehydrogenase Kinase 3: Implication in Lung Cancer Therapy
Design and development of potential pyruvate dehydrogenase kinase 3 (PDK3) inhibitors have gained attention because of their possible therapeutic uses in lung cancer therapy. In the present study, the binding affinity of naturally occurring alkaloids, hordenine, vincamine, tryptamine, cinchonine, an...
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MDPI AG
2020-05-01
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| Series: | Biomedicines |
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| Online Access: | https://www.mdpi.com/2227-9059/8/5/119 |
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| author | Saleha Anwar Taj Mohammad Anas Shamsi Aarfa Queen Shahnaz Parveen Suaib Luqman Gulam Mustafa Hasan Khalid A. Alamry Naved Azum Abdullah M. Asiri Md. Imtaiyaz Hassan |
| author_facet | Saleha Anwar Taj Mohammad Anas Shamsi Aarfa Queen Shahnaz Parveen Suaib Luqman Gulam Mustafa Hasan Khalid A. Alamry Naved Azum Abdullah M. Asiri Md. Imtaiyaz Hassan |
| author_sort | Saleha Anwar |
| collection | DOAJ |
| description | Design and development of potential pyruvate dehydrogenase kinase 3 (PDK3) inhibitors have gained attention because of their possible therapeutic uses in lung cancer therapy. In the present study, the binding affinity of naturally occurring alkaloids, hordenine, vincamine, tryptamine, cinchonine, and colcemid was measured with PDK3. The molecular docking and fluorescence binding studies suggested that all these compounds show a considerable binding affinity for PDK3. Among them, the affinity of hordenine to the PDK3 was excellent (<i>K</i> = 10<sup>6</sup> M<sup>−1</sup>) which was further complemented by isothermal titration calorimetric measurements. Hordenine binds in the active site pocket of PDK3 and forms a significant number of non-covalent interactions with functionally important residues. All-atom molecular dynamics (MD) simulation study suggested that the PDK3-hordenine complex is stabilized throughout the trajectory of 100ns and leads to fewer conformational changes. The enzyme inhibition studies showed that hordenine inhibits the activity of PDK3 with an IC<sub>50</sub> value of 5.4 µM. Furthermore, hordenine showed a cytotoxic effect on human lung cancer cells (A549 and H1299) with an admirable IC<sub>50</sub> value. However, it did not inhibit the growth of HEK293 cells up to 200 µM, indicating its non-toxicity to non-cancerous cell lines. In summary, our findings provide the basis for the therapeutic implication of hordenine and its derivatives in lung cancer and PDK3-related diseases after required in vivo validation. |
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| institution | Directory Open Access Journal |
| issn | 2227-9059 |
| language | English |
| last_indexed | 2024-03-10T19:50:34Z |
| publishDate | 2020-05-01 |
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| series | Biomedicines |
| spelling | doaj.art-5cd98847cadc41ebb7e6612c4121b1c92023-11-20T00:23:15ZengMDPI AGBiomedicines2227-90592020-05-018511910.3390/biomedicines8050119Discovery of Hordenine as a Potential Inhibitor of Pyruvate Dehydrogenase Kinase 3: Implication in Lung Cancer TherapySaleha Anwar0Taj Mohammad1Anas Shamsi2Aarfa Queen3Shahnaz Parveen4Suaib Luqman5Gulam Mustafa Hasan6Khalid A. Alamry7Naved Azum8Abdullah M. Asiri9Md. Imtaiyaz Hassan10Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, Jamia Nagar, New Delhi 110025, IndiaCentre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, Jamia Nagar, New Delhi 110025, IndiaCentre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, Jamia Nagar, New Delhi 110025, IndiaDepartment of Chemistry, Jamia Millia Islamia, Jamia Nagar, New Delhi 110025, IndiaMolecular Bioprospection Department, CSIR-Central Institute of Medicinal and Aromatic Plants, Lucknow 226015, IndiaMolecular Bioprospection Department, CSIR-Central Institute of Medicinal and Aromatic Plants, Lucknow 226015, IndiaDepartment of Biochemistry, College of Medicine, Prince Sattam Bin Abdulaziz University, P.O. Box 173, Al-Kharj 11942, Saudi ArabiaChemistry Department, Faculty of Science, King Abdulaziz University, P.O. Box 80203, Jeddah 21589, Saudi ArabiaChemistry Department, Faculty of Science, King Abdulaziz University, P.O. Box 80203, Jeddah 21589, Saudi ArabiaChemistry Department, Faculty of Science, King Abdulaziz University, P.O. Box 80203, Jeddah 21589, Saudi ArabiaCentre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, Jamia Nagar, New Delhi 110025, IndiaDesign and development of potential pyruvate dehydrogenase kinase 3 (PDK3) inhibitors have gained attention because of their possible therapeutic uses in lung cancer therapy. In the present study, the binding affinity of naturally occurring alkaloids, hordenine, vincamine, tryptamine, cinchonine, and colcemid was measured with PDK3. The molecular docking and fluorescence binding studies suggested that all these compounds show a considerable binding affinity for PDK3. Among them, the affinity of hordenine to the PDK3 was excellent (<i>K</i> = 10<sup>6</sup> M<sup>−1</sup>) which was further complemented by isothermal titration calorimetric measurements. Hordenine binds in the active site pocket of PDK3 and forms a significant number of non-covalent interactions with functionally important residues. All-atom molecular dynamics (MD) simulation study suggested that the PDK3-hordenine complex is stabilized throughout the trajectory of 100ns and leads to fewer conformational changes. The enzyme inhibition studies showed that hordenine inhibits the activity of PDK3 with an IC<sub>50</sub> value of 5.4 µM. Furthermore, hordenine showed a cytotoxic effect on human lung cancer cells (A549 and H1299) with an admirable IC<sub>50</sub> value. However, it did not inhibit the growth of HEK293 cells up to 200 µM, indicating its non-toxicity to non-cancerous cell lines. In summary, our findings provide the basis for the therapeutic implication of hordenine and its derivatives in lung cancer and PDK3-related diseases after required in vivo validation.https://www.mdpi.com/2227-9059/8/5/119pyruvate dehydrogenase kinasekinase inhibitorsdrug design and discoverylung cancer therapymolecular dynamics simulationhordenine |
| spellingShingle | Saleha Anwar Taj Mohammad Anas Shamsi Aarfa Queen Shahnaz Parveen Suaib Luqman Gulam Mustafa Hasan Khalid A. Alamry Naved Azum Abdullah M. Asiri Md. Imtaiyaz Hassan Discovery of Hordenine as a Potential Inhibitor of Pyruvate Dehydrogenase Kinase 3: Implication in Lung Cancer Therapy Biomedicines pyruvate dehydrogenase kinase kinase inhibitors drug design and discovery lung cancer therapy molecular dynamics simulation hordenine |
| title | Discovery of Hordenine as a Potential Inhibitor of Pyruvate Dehydrogenase Kinase 3: Implication in Lung Cancer Therapy |
| title_full | Discovery of Hordenine as a Potential Inhibitor of Pyruvate Dehydrogenase Kinase 3: Implication in Lung Cancer Therapy |
| title_fullStr | Discovery of Hordenine as a Potential Inhibitor of Pyruvate Dehydrogenase Kinase 3: Implication in Lung Cancer Therapy |
| title_full_unstemmed | Discovery of Hordenine as a Potential Inhibitor of Pyruvate Dehydrogenase Kinase 3: Implication in Lung Cancer Therapy |
| title_short | Discovery of Hordenine as a Potential Inhibitor of Pyruvate Dehydrogenase Kinase 3: Implication in Lung Cancer Therapy |
| title_sort | discovery of hordenine as a potential inhibitor of pyruvate dehydrogenase kinase 3 implication in lung cancer therapy |
| topic | pyruvate dehydrogenase kinase kinase inhibitors drug design and discovery lung cancer therapy molecular dynamics simulation hordenine |
| url | https://www.mdpi.com/2227-9059/8/5/119 |
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