In-silico Investigations of quinine and quinidine as potential Inhibitors of AKR1B1 and AKR1B10: Functional and structural characterization.

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  • Additional Information
    • Source:
      Publisher: Public Library of Science Country of Publication: United States NLM ID: 101285081 Publication Model: eCollection Cited Medium: Internet ISSN: 1932-6203 (Electronic) Linking ISSN: 19326203 NLM ISO Abbreviation: PLoS One Subsets: MEDLINE
    • Publication Information:
      Original Publication: San Francisco, CA : Public Library of Science
    • Subject Terms:
      Aldehyde Reductase*/antagonists & inhibitors ; Aldo-Keto Reductases*/antagonists & inhibitors ; Colonic Neoplasms*/drug therapy ; Quinidine*/pharmacology ; Quinine*/pharmacology; Humans ; Molecular Docking Simulation
    • Abstract:
      The aberrant expression of aldo keto reductases (AKR1B1 & AKR1B10) has been extensively studied in different types of cancer especially the colon cancer but a very few studies have yet been reported regarding the discovery of inhibitors for the treatment of colon cancer by targeting these isozymes. Therefore, there is a need of selective inhibitors of both targets for the eradication of colon cancer. Currently, the study is focused on the exploration of two quinolone compounds i.e., (S)-(6-Methoxyquinolin-4-yl)[(1S,2R,4S,5R)-5-vinylquinuclidin-2-yl]methanol (Quinidine) and (R)-(6-Methoxyquinolin-4-yl)[(1S,2S,4S,5R)-5-vinylquinuclidin-2-yl]methanol (Quinine) as the potential inhibitors of AKR1B1 and AKR1B10 via detailed in-silico approach. The structural properties including vibrational frequencies, dipole moment, polarizability and the optimization energies were estimated using density functional theory (DFT) calculations; where both compounds were found chemically reactive. After that, the optimized structures were used for the molecular docking studies and here quinidine was found more selective towards AKR1B1 and quinine exhibited maximum inhibition of AKR1B10. The results of molecular docking studies were validated by molecular dynamics simulations which provided the deep insight of stability of protein ligand complex. At the end, the ADMET properties were determined to demonstrate the druglikeness properties of both selected compounds. These findings suggested further exploration of both compounds at molecular level using different in-vivo and in-vitro approaches that will lead to the designing of potential inhibitor of AKR1B1/AKR1B10 for curing colon cancer and related malignancies.
      Competing Interests: The authors have declared that no competing interests exist.
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    • Accession Number:
      EC 1.1.1.21 (AKR1B1 protein, human)
      EC 1.1.1.- (AKR1B10 protein, human)
      EC 1.1.1.21 (Aldehyde Reductase)
      EC 1.1.1.- (Aldo-Keto Reductases)
      ITX08688JL (Quinidine)
      A7V27PHC7A (Quinine)
    • Publication Date:
      Date Created: 20221027 Date Completed: 20221101 Latest Revision: 20221101
    • Publication Date:
      20221213
    • Accession Number:
      PMC9612481
    • Accession Number:
      10.1371/journal.pone.0271602
    • Accession Number:
      36301939