Abstract

Obesity is a complex, chronic disease that requires a multifaceted approach. This research focuses on evaluating the anti-obesity efficacy and potential toxicity of natural compounds and approved drugs through computational docking and LD50 analysis. The study included 20 compounds, such as phentermine and topiramate, as well as flavonoids, phenolic acids, and other natural substances, prepared for molecular docking using the Ligprep module. The PDB ID 6C9F crystal structures related to obesity were obtained for docking using Glide in Schrödinger Suite 2023. The ADMET properties were predicted using SwissADME and ProTox-II servers. Docking scores ranged from -9.809 to -3.561, with flavonoids like isoquercetin, rutin, astragalin, quercetin, and kaempferol showing the strongest binding affinities. LD50 values spanned from 28 mg/kg for benzaldehyde to 5000 mg/kg for several flavonoids and phenolic acids. Phentermine fell into toxicity class 3, while topiramate was class 5. Flavonoids, which exhibited strong docking scores, tended to have lower toxicity classes. Molecular docking revealed key interactions, with phentermine and topiramate binding to GLU 102, and flavonoids interacting with multiple amino acids, such as GLU 102, ASN 146, and LYS 47. ADME analysis showed that phentermine had the lowest molecular weight (149.23 g/mol) and high GI absorption, whereas flavonoids had higher molecular weights (286.24 to 610.52 g/mol) and lower GI absorption. Only phentermine crossed the blood-brain barrier (BBB). Phentermine had fewer drug-likeness violations and alerts for PAINS and Brenk compared to flavonoids, indicating better drug- likeness and ease of synthesis (synthetic accessibility score of 1). However, compounds like phentermine, benzyl benzoate, and coumarin showed higher toxicity and neurotoxic potential, with risks for neurologic disorders, carcinogenicity, and ecotoxicity. Flavonoids like quercetin, kaempferol, and caffeic acid demonstrated safer profiles, suggesting potential applications in medicine and nutrition

Keywords

toxicology, anti-obesity, Protein