Cryo-EM structure enabling virtual screening for the discovery of highly potent TRPM3 antagonists with analgesic efficacy.

Current analgesics are limited by insufficient efficacy and adverse effects. TRPM3, a non-opioid target expressed in sensory neurons, represents a promising yet challenging therapeutic avenue due to a lack of potent, selective antagonists and unresolved structural pharmacology. We determined cryo-electron microscopy (cryo-EM) structures of human TRPM3, identifying a compact ligand-binding pocket that enabled large-scale virtual screening. Structure-based lead optimization yielded a picomolar antagonist with favorable drug-like properties. This compound exhibited potent, dose-dependent analgesia across multiple rodent models of neuropathic and migraine pain. Our work establishes a structure-based discovery pipeline for TRP channels, delivering a high-potency antagonist that validates TRPM3 as a therapeutic target and provides a framework for rational drug design against other ion channels.