ArticleFrontiers in pharmacology2025
Pharmacophore-based virtual screening and
Article in Frontiers in pharmacology, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
Introduction: 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's PF-06835919 has progressed to phase II trials, demonstrating a reduction in liver fat and improved insulin sensitivity, while Eli Lilly's 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. Methods: 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. Results: Ten compounds exhibited docking scores ranging from -7.79 to -9.10 kcal/mol, surpassing those of the compounds currently undergoing clinical trials, PF-06835919 (-7.768 kcal/mol) and LY-3522348 (-6.54 kcal/mol). Their calculated binding free energies ranged from -57.06 to -70.69 kcal/mol, further demonstrating their superiority over PF-06835919 (-56.71 kcal/mol) and LY-3522348 (-45.15 kcal/mol). ADMET profiling refined the selection to five compounds ( Conclusion: These findings highlight compound
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