Opioids that stimulate the μ-opioid receptor (MOR1) are the most frequently 
prescribed and effective analgesics. Here we present a structural model of MOR1. 
Molecular dynamics simulations show a ligand-dependent increase in the 
conformational flexibility of the third intracellular loop that couples with the 
G protein complex. These simulations likewise identified residues that form 
frequent contacts with ligands. We validated the binding residues using 
site-directed mutagenesis coupled with radioligand binding and functional 
assays. The model was used to blindly screen a library of ∼1.2 million 
compounds. From the 34 compounds predicted to be strong binders, the top three 
candidates were examined using biochemical assays. One compound showed high 
efficacy and potency. Post hoc testing revealed this compound to be nalmefene, a 
potent clinically used antagonist, thus further validating the model. In 
summary, the MOR1 model provides a tool for elucidating the structural mechanism 
of ligand-initiated cell signaling and for screening novel analgesics.