{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,17]],"date-time":"2026-10-17T20:04:57Z","timestamp":1792267497076,"version":"4.4.0"},"reference-count":93,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,4,7]],"date-time":"2025-04-07T00:00:00Z","timestamp":1743984000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Excessive fructose consumption is a significant driver of metabolic disorders, including obesity, diabetes, non-alcoholic fatty liver disease and non-alcoholic steatohepatitis primarily by promoting insulin resistance and fat accumulation. Ketohexokinase C (KHK-C), a pivotal enzyme in fructose metabolism, catalyzes the phosphorylation of fructose to fructose-1-phosphate, initiating a cascade of downstream metabolic processes. In contrast to glucose metabolism, KHK-C lacks negative feedback regulation, allowing the continuous phosphorylation of fructose, which leads to heightened levels of glucose, glycogen, and triglycerides in the bloodstream and liver. While targeting KHK-C offers a promising therapeutic avenue, no drugs have yet been approved for clinical use. Pfizer\u2019s PF-06835919 has progressed to phase II trials, demonstrating a reduction in liver fat and improved insulin sensitivity, while Eli Lilly\u2019s LY-3522348 also shows significant potential. Nonetheless, there remains a critical need for the development of novel KHK-C inhibitors that offer improved pharmacokinetics, enhanced efficacy, and superior safety profiles.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>In the present study, a comprehensive computational strategy was employed to screen 460,000 compounds from the National Cancer Institute library for potential KHK-C inhibitors. Initially, pharmacophore-based virtual screening was used to identify potential hits, followed by multi-level molecular docking, binding free energy estimation, pharmacokinetic analysis, and molecular dynamics (MD) simulations to further evaluate the compounds. This multi-step approach aimed to identify compounds with strong binding affinity, favorable pharmacokinetic profiles, and high potential for efficacy as KHK-C inhibitors.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Ten compounds exhibited docking scores ranging from \u22127.79 to \u22129.10\u00a0kcal\/mol, surpassing those of the compounds currently undergoing clinical trials, PF-06835919 (\u22127.768\u00a0kcal\/mol) and LY-3522348 (\u22126.54\u00a0kcal\/mol). Their calculated binding free energies ranged from \u221257.06 to \u221270.69\u00a0kcal\/mol, further demonstrating their superiority over PF-06835919 (\u221256.71\u00a0kcal\/mol) and LY-3522348 (\u221245.15\u00a0kcal\/mol). ADMET profiling refined the selection to five compounds (\n                      <jats:bold>1<\/jats:bold>\n                      ,\n                      <jats:bold>2,<\/jats:bold>\n                      and\n                      <jats:bold>4\u20136<\/jats:bold>\n                      ), and molecular dynamics simulations identified compound\n                      <jats:bold>2<\/jats:bold>\n                      as the most stable and promising candidate compared to the clinical candidate PF-06835919.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      These findings highlight compound\n                      <jats:bold>2<\/jats:bold>\n                      as a potent KHK-C inhibitor with predicted pharmacokinetics and toxicity profiles supporting its potential for treating fructose-driven metabolic disorders, warranting further validation.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fphar.2025.1531512","type":"journal-article","created":{"date-parts":[[2025,4,7]],"date-time":"2025-04-07T01:14:18Z","timestamp":1743988458000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":8,"title":["Pharmacophore-based virtual screening and in silico investigations of small molecule library for discovery of human hepatic ketohexokinase inhibitors for the treatment of fructose metabolic disorders"],"prefix":"10.3389","volume":"16","author":[{"given":"Tilal","family":"Elsaman","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Magdi Awadalla","family":"Mohamed","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abozer Y.","family":"Elderdery","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abdullah","family":"Alsrhani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Badr","family":"Alzahrani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heba Bassiony","family":"Ghanem","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeremy","family":"Mills","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Musaed","family":"Rayzah","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nasser A. 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