<i>In silico</i> characterization of MC4R variants reveals insights into Setmelanotide pharmacogenomics and personalized medicine for obesity

AIMS: The Melanocortin-4 receptor is a key regulator of energy homeostasis, and loss-of-function variants are the most common cause of monogenic obesity. This study aimed to characterize MC4R genetic variants and evaluate their potential impact on receptor function and interaction with Setmelanotide. MATERIALS AND METHODS: approach was applied to analyze MC4R single nucleotide polymorphisms (SNPs). Variants were retrieved from ClinVar and dbSNP and evaluated using PredictSNP and complementary tools to assess evolutionary conservation, protein stability, and structural and functional effects. Structural modeling and interaction analyses were performed to investigate receptor-ligand binding. RESULTS: Among 84 ClinVar variants, 15 were predicted as deleterious, while 10 of 350 dbSNP variants showed similar predictions. A total of 25 variants were further analyzed, revealing effects on protein stability, conserved residues, and structural conformation. Interaction modeling identified key amino acids involved in Setmelanotide binding and suggested that specific variants may influence receptor-agonist interactions. CONCLUSIONS: These findings provide insights into the structural and functional consequences of MC4R variants and highlight their potential relevance for pharmacogenomic studies, supporting future experimental validation in MC4R-related obesity.