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

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 (∆G_bind = - 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.