Neuron · 2026
Cryo-EM structure enabling virtual screening for the discovery of highly potent TRPM3 antagonists with analgesic efficacy.
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Yang Tingting, Che Tong, Guo Hongmin, Cheng Xinyu, Wang Mingyang, Lv Sijia, Yang Xiaoqiang, Wu Xiaoyun, Liu Yinzhen, Liu Hui, Hu Han, Li Wenlu, Wan Shuangyan, Peng Haoxiang, Nan Weiwei, Zhang Yuting, Zeng Bo, Neher Erwin, Liu Ougen, Yu Bo, Li Fengxian, Li Guilin, Li Jian, Duan Jingjing, Zhang Jin
Аннотация
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.