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<p>Obesity requires innovative multi-target therapeutic strategies. This study explores Fmol021 as a novel oral potential multiple agonist targeting the GLP-1 receptor and key metabolic nodes. The methodology integrated the identification of 50 obesity-related genes via network pharmacology, followed by an in silico screening of over 2000 docking simulations. Among the candidates, Fmol021 showed binding affinities potentially comparable to clinical-stage oral agonists like danuglipron and lotiglipron. To further investigate the potential of this candidate, 50&#xa0;ns all-atom molecular dynamics and MM-GBSA calculations were performed. Fmol021 exhibited structural stability within the GLP-1R orthosteric pocket (RMSD ≈ 0.9&#xa0;nm) and a favorable binding free energy (<i>∆G</i><sub><i>bind</i></sub> = − 39.44&#xa0;kcal/mol) compared to danuglipron. Beyond incretin signaling, Fmol021 showed in silico indications of a multi-target mechanism involving the potential activation of Sestrin2 and modulation of DYRK1A, addressing obesity through both metabolic and antioxidant pathways. Furthermore, Fmol021 exhibited a favorable predicted safety profile with an <i>LD</i><sub><i>50</i></sub> of 2000&#xa0;mg/kg and no predicted hepatotoxicity, alongside full compliance with Lipinski’s rule of five for oral bioavailability. While these in silico findings provide a preliminary rationale for Fmol021 as a breakthrough multifunctional candidate, further in vitro and in vivo studies are essential to confirm its therapeutic efficacy and safety.</p>

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Identification of a novel oral potential multiple agonist for obesity treatment: multi-target in silico study

  • 期刊论文

  • 发表日期：

    2026年5月21日

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  • Álvaro Galiano,
  • Fernando Notario-Pérez

摘要

Obesity requires innovative multi-target therapeutic strategies. This study explores Fmol021 as a novel oral potential multiple agonist targeting the GLP-1 receptor and key metabolic nodes. The methodology integrated the identification of 50 obesity-related genes via network pharmacology, followed by an in silico screening of over 2000 docking simulations. Among the candidates, Fmol021 showed binding affinities potentially comparable to clinical-stage oral agonists like danuglipron and lotiglipron. To further investigate the potential of this candidate, 50 ns all-atom molecular dynamics and MM-GBSA calculations were performed. Fmol021 exhibited structural stability within the GLP-1R orthosteric pocket (RMSD ≈ 0.9 nm) and a favorable binding free energy (∆Gbind = − 39.44 kcal/mol) compared to danuglipron. Beyond incretin signaling, Fmol021 showed in silico indications of a multi-target mechanism involving the potential activation of Sestrin2 and modulation of DYRK1A, addressing obesity through both metabolic and antioxidant pathways. Furthermore, Fmol021 exhibited a favorable predicted safety profile with an LD50 of 2000 mg/kg and no predicted hepatotoxicity, alongside full compliance with Lipinski’s rule of five for oral bioavailability. While these in silico findings provide a preliminary rationale for Fmol021 as a breakthrough multifunctional candidate, further in vitro and in vivo studies are essential to confirm its therapeutic efficacy and safety.