Melatonin initiates physiologic and therapeutic responses in various tissues through binding to poorly defined MT receptors regulated by G-proteins and purine nucleotides. Melatonin's interaction with other G-protein regulated receptors, including those of serotonin, is unclear. This study explores the potential for the interaction of melatonin with nucleotide and receptor ligand structures.The study uses a computational program to investigate relative molecular similarity by the comparative superimposition and quantitative fitting of molecular structures to adenine and guanine nucleotide templates.A minimum energy melatonin conformer replicates the nucleotide fits of ligand structures that regulate Gαi and Gαq proteins via serotonin, dopamine, opioid, α-adrenoceptor, and muscarinic receptor classes. The same conformer also replicates the nucleotide fits of ligand structures regulating K+ and Ca2+ ion channels. The acyl-methoxy distance within the melatonin conformer matches a carbonyl-hydroxyl distance in guanine nucleotide.Molecular similarity within the melatonin and ligand structures relates to the established effects of melatonin on cell receptors regulated by purine nucleotides in cell signal transduction processes. Pharmacologic receptor promiscuity may contribute to the widespread effects of melatonin.