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Discovery of Hordenine as a Potential Inhibitor of Pyruvate Dehydrogenase Kinase 3: Implication in Lung Cancer Therapy

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Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, Jamia Nagar, New Delhi 110025, India
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Department of Chemistry, Jamia Millia Islamia, Jamia Nagar, New Delhi 110025, India
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Molecular Bioprospection Department, CSIR-Central Institute of Medicinal and Aromatic Plants, Lucknow 226015, India
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Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
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Department of Biochemistry, College of Medicine, Prince Sattam Bin Abdulaziz University, P.O. Box 173, Al-Kharj 11942, Saudi Arabia
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Chemistry Department, Faculty of Science, King Abdulaziz University, P.O. Box 80203, Jeddah 21589, Saudi Arabia
7
Center of Excellence for Advanced Materials Research (CEAMR), King Abdulaziz University, P.O. Box 80203, Jeddah 21589, Saudi Arabia
*
Author to whom correspondence should be addressed.
Biomedicines 2020, 8(5), 119; https://doi.org/10.3390/biomedicines8050119
Received: 14 April 2020 / Revised: 9 May 2020 / Accepted: 11 May 2020 / Published: 14 May 2020
(This article belongs to the Special Issue Innate Immunity Orchestration in Lung Health and Diseases)
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 (K = 106 M−1) 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 IC50 value of 5.4 µM. Furthermore, hordenine showed a cytotoxic effect on human lung cancer cells (A549 and H1299) with an admirable IC50 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. View Full-Text
Keywords: pyruvate dehydrogenase kinase; kinase inhibitors; drug design and discovery; lung cancer therapy; molecular dynamics simulation; hordenine pyruvate dehydrogenase kinase; kinase inhibitors; drug design and discovery; lung cancer therapy; molecular dynamics simulation; hordenine
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Anwar, S.; Mohammad, T.; Shamsi, A.; Queen, A.; Parveen, S.; Luqman, S.; Hasan, G.M.; Alamry, K.A.; Azum, N.; Asiri, A.M.; Hassan, M.I. Discovery of Hordenine as a Potential Inhibitor of Pyruvate Dehydrogenase Kinase 3: Implication in Lung Cancer Therapy. Biomedicines 2020, 8, 119.

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