Integrated In Silico and In Vivo Assessment of Weight Management Agents Setmanlotide and Orforglipron and Natural Products Berberine and Capsicum

Abstract

Obesity is a growing global health challenge and a major contributor to metabolic syndrome, type 2 diabetes mellitus, and cardiovascular diseases. The present study aimed to comprehensively evaluate the efficacy, mechanisms of action, safety profiles, and pharmacokinetic characteristics of selected weight management agents, namely Setmelanotide, Orforglipron, Berberine, and Capsicum, through integrated in vivo and in silico approaches. A systematic review of published experimental and clinical studies was conducted to assess therapeutic outcomes related to body weight reduction, appetite regulation, lipid metabolism, and energy expenditure. Computational analyses were subsequently performed using SwissADME, ProTox II, and PASS Online platforms to predict absorption, distribution, metabolism, excretion, toxicity, and biological activity profiles of the investigated compounds. The findings demonstrated that Setmelanotide and Orforglipron exhibited significant anti-obesity potential through modulation of appetite signaling pathways and metabolic regulation. Berberine and Capsicum showed moderate but clinically relevant effects on weight reduction and metabolic enhancement, with comparatively favorable safety and tolerability profiles. In silico evaluation indicated acceptable pharmacokinetic properties for most compounds, while peptide associated structural complexity limited the predictive assessment of Setmelanotide. Toxicity prediction models suggested low to moderate toxicity risks among the evaluated agents. Overall, the integration of experimental evidence with computational modeling provides a comprehensive framework for understanding the therapeutic potential of synthetic and natural weight management agents. These findings support their prospective application in evidence based obesity management and future pharmacological development.