Fig. 3. Structure-based discovery and optimization of a G protein–biased μ-OR ligand, PZM21.

Schematic representation of the discovery and optimization pipeline using structure-guided virtual screening. Using the crystal structure of the μ-OR, a large set of chemical compounds was virtually screened, which was followed by the identification of a handful of lead compounds for further testing. Subsequent optimization and structure-function relationship studies yielded PZM21, which is a G protein–biased μ-OR partial agonist, and produced desirable analgesic activity in vivo without the typical side effects observed with other μ-OR agonists, such as morphine.