Examining Prenylated Xanthones as Potential Inhibitors Against Ketohexokinase C Isoform for the Treatment of Fructose-Driven Metabolic Disorders: An Integrated Computational Approach
<b>Background/Objectives:</b> Fructose-driven metabolic disorders, such as obesity, non-alcoholic fatty liver disease (NAFLD), dyslipidemia, and type 2 diabetes, are significant global health challenges. Ketohexokinase C (KHK-C), a key enzyme in fructose metabolism, is a promising therap...
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MDPI AG
2025-01-01
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| author | Tilal Elsaman Magdi Awadalla Mohamed |
| author_facet | Tilal Elsaman Magdi Awadalla Mohamed |
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| description | <b>Background/Objectives:</b> Fructose-driven metabolic disorders, such as obesity, non-alcoholic fatty liver disease (NAFLD), dyslipidemia, and type 2 diabetes, are significant global health challenges. Ketohexokinase C (KHK-C), a key enzyme in fructose metabolism, is a promising therapeutic target. α-Mangostin, a naturally occurring prenylated xanthone, has been identified as an effective KHK-C inhibitor, prompting exploration of its analogs for enhanced efficacy. This study aimed to identify α-Mangostin analogs with improved inhibitory properties against KHK-C to address these disorders. <b>Methods:</b> A library of 1383 analogs was compiled from chemical databases and the literature. Molecular docking, binding free energy calculations, pharmacokinetic assessments, molecular dynamics simulations, and quantum mechani–cal analyses were used to screen and evaluate the compounds. α-Mangostin’s binding affinity (37.34 kcal/mol) served as the benchmark. <b>Results:</b> Sixteen analogs demonstrated binding affinities superior to α-Mangostin (from −45.51 to −61.3 kcal/mol), LY-3522348 (−45.36 kcal/mol), and reported marine-derived inhibitors (from −22.74 to −51.83 kcal/mol). Hits <b>7</b>, <b>8</b>, <b>9</b>, <b>13</b>, and <b>15</b> not only surpassed these benchmarks in binding affinity, but also exhibited superior pharmacokinetic properties compared to α-Mangostin, LY-3522348, and marine-derived inhibitors, indicating strong in vivo potential. Among these, hit <b>8</b> emerged as the best performer, achieving a binding free energy of −61.30 kcal/mol, 100% predicted oral absorption, enhanced metabolic stability, and stable molecular dynamics. <b>Conclusions:</b> Hit <b>8</b> emerged as the most promising candidate due to its superior binding affinity, favorable pharmacokinetics, and stable interactions with KHK-C. These findings highlight its potential for treating fructose-driven metabolic disorders, warranting further experimental validation. |
| format | Article |
| id | doaj-art-9c9445b8e80f4dfd8cca659e51219110 |
| institution | Kabale University |
| issn | 1424-8247 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | MDPI AG |
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| series | Pharmaceuticals |
| spelling | doaj-art-9c9445b8e80f4dfd8cca659e512191102025-01-24T13:45:29ZengMDPI AGPharmaceuticals1424-82472025-01-0118112610.3390/ph18010126Examining Prenylated Xanthones as Potential Inhibitors Against Ketohexokinase C Isoform for the Treatment of Fructose-Driven Metabolic Disorders: An Integrated Computational ApproachTilal Elsaman0Magdi Awadalla Mohamed1Department of Pharmaceutical Chemistry, College of Pharmacy, Jouf University, Sakaka 72388, Saudi ArabiaDepartment of Pharmaceutical Chemistry, College of Pharmacy, Jouf University, Sakaka 72388, Saudi Arabia<b>Background/Objectives:</b> Fructose-driven metabolic disorders, such as obesity, non-alcoholic fatty liver disease (NAFLD), dyslipidemia, and type 2 diabetes, are significant global health challenges. Ketohexokinase C (KHK-C), a key enzyme in fructose metabolism, is a promising therapeutic target. α-Mangostin, a naturally occurring prenylated xanthone, has been identified as an effective KHK-C inhibitor, prompting exploration of its analogs for enhanced efficacy. This study aimed to identify α-Mangostin analogs with improved inhibitory properties against KHK-C to address these disorders. <b>Methods:</b> A library of 1383 analogs was compiled from chemical databases and the literature. Molecular docking, binding free energy calculations, pharmacokinetic assessments, molecular dynamics simulations, and quantum mechani–cal analyses were used to screen and evaluate the compounds. α-Mangostin’s binding affinity (37.34 kcal/mol) served as the benchmark. <b>Results:</b> Sixteen analogs demonstrated binding affinities superior to α-Mangostin (from −45.51 to −61.3 kcal/mol), LY-3522348 (−45.36 kcal/mol), and reported marine-derived inhibitors (from −22.74 to −51.83 kcal/mol). Hits <b>7</b>, <b>8</b>, <b>9</b>, <b>13</b>, and <b>15</b> not only surpassed these benchmarks in binding affinity, but also exhibited superior pharmacokinetic properties compared to α-Mangostin, LY-3522348, and marine-derived inhibitors, indicating strong in vivo potential. Among these, hit <b>8</b> emerged as the best performer, achieving a binding free energy of −61.30 kcal/mol, 100% predicted oral absorption, enhanced metabolic stability, and stable molecular dynamics. <b>Conclusions:</b> Hit <b>8</b> emerged as the most promising candidate due to its superior binding affinity, favorable pharmacokinetics, and stable interactions with KHK-C. These findings highlight its potential for treating fructose-driven metabolic disorders, warranting further experimental validation.https://www.mdpi.com/1424-8247/18/1/126xanthonesfructoseketohexokinase Cobesitydiabetesdyslipidemia |
| spellingShingle | Tilal Elsaman Magdi Awadalla Mohamed Examining Prenylated Xanthones as Potential Inhibitors Against Ketohexokinase C Isoform for the Treatment of Fructose-Driven Metabolic Disorders: An Integrated Computational Approach Pharmaceuticals xanthones fructose ketohexokinase C obesity diabetes dyslipidemia |
| title | Examining Prenylated Xanthones as Potential Inhibitors Against Ketohexokinase C Isoform for the Treatment of Fructose-Driven Metabolic Disorders: An Integrated Computational Approach |
| title_full | Examining Prenylated Xanthones as Potential Inhibitors Against Ketohexokinase C Isoform for the Treatment of Fructose-Driven Metabolic Disorders: An Integrated Computational Approach |
| title_fullStr | Examining Prenylated Xanthones as Potential Inhibitors Against Ketohexokinase C Isoform for the Treatment of Fructose-Driven Metabolic Disorders: An Integrated Computational Approach |
| title_full_unstemmed | Examining Prenylated Xanthones as Potential Inhibitors Against Ketohexokinase C Isoform for the Treatment of Fructose-Driven Metabolic Disorders: An Integrated Computational Approach |
| title_short | Examining Prenylated Xanthones as Potential Inhibitors Against Ketohexokinase C Isoform for the Treatment of Fructose-Driven Metabolic Disorders: An Integrated Computational Approach |
| title_sort | examining prenylated xanthones as potential inhibitors against ketohexokinase c isoform for the treatment of fructose driven metabolic disorders an integrated computational approach |
| topic | xanthones fructose ketohexokinase C obesity diabetes dyslipidemia |
| url | https://www.mdpi.com/1424-8247/18/1/126 |
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