Approximately 35% of approved drugs target G protein-coupled receptors (GPCRs). GPCRs interact with each other to form homo and/or heterodimers. Their pharmacological properties are different from those of monomers. According to some previous research, the pharmacological properties of the dimers could be modulated by the administration of small molecules. There are also increasing reports on ligands that bind to hetero-dimers and their pharmacological properties. For example, δ-μ opioid receptor hetero-dimer (OPRD1-OPRM1 heterodimer) ligand, CYM 51010, was confirmed to be as effective as morphine but less likely to cause tolerance than morphine [1]. In addition, 993 ligands binding to the OPRD1-OPRM1 hetero-dimer are available in the PubChem database. However, there are some open questions, such as whether these ligands bind to OPRD1, OPRM1 or both, whether heterodimer formation is ligand-dependent or not, and what properties of the ligands contribute to binding to the heterodimer. We applied unsupervised learning to analyze the OPRD1-OPRM1 heterodimeric ligands and canonical opioid receptor ligands, and report on the characteristics of the heterodimeric ligands.
 
[1] Gomes et al., Proc Natl Acad Sci USA. 2013;110:12072-7