9L3F

Structure-Guided Design of Picomolar-level Macrocyclic TRPC5 Channel Inhibitors with Antidepressant Activity

This is a non-PDB format compatible entry.

Summary for 9L3F

• Entry DOI: 10.2210/pdb9l3f/pdb
• EMDB information: 62784
• Descriptor: Short transient receptor potential channel 5, ZINC ION, CALCIUM ION, ... (4 entities in total)
• Functional Keywords: ion channel, trpc5, inhibitor, membrane protein
• Biological source: Mus musculus (house mouse)
• Total number of polymer chains: 4
• Total formula weight: 358208.58

Authors

Che, T.,Zhang, J.,Xiong, B.,Cheng, X.Y. (deposition date: 2024-12-18, release date: 2025-12-24, Last modification date: 2026-02-18)

Primary citation

Che, T.,Chen, Y.,Cheng, X.,Hu, H.,Wu, X.,Zhang, Y.,Yang, X.,Liu, Y.,Liu, H.,Nan, W.,Wan, S.,Yang, M.,Zeng, B.,Li, J.,Zhang, J.,Xiong, B.
Structure-guided design of picomolar-level macrocyclic TRPC5 channel inhibitors with antidepressant activity.
Acta Pharm Sin B, 16:371-386, 2026

PubMed Abstract: Recent advances in ion channel structural biology have enhanced structure-based drug design, yet lipid-occupied binding pockets-often large and flat-remain a major hurdle for developing selective small molecules. TRPC5, a brain-enriched channel regulating depression and anxiety, is a promising therapeutic target, but current preclinical candidates suffer from moderate off-target effects. To address this, we designed macrocyclic TRPC5 inhibitors using structure-guided macrocyclization, overcoming lipid-binding site challenges. Among these, JDIC-127 exhibited unprecedented potency with IC of 374 pmol/L-200-fold more potent than HC-070-and exceptional selectivity. Its specificity arises from interactions with unique structural features near the S5 and S6 helices of TRPC5, minimizing activity against related TRPC channels and other ion channels. This selective inhibition aligns with preclinical evidence supporting JDIC-127's potential in treating neuropsychiatric disorders. The study demonstrates how macrocycles stabilize ligand conformations, enhance affinity, and achieve selectivity in lipid-dominated binding sites. It also highlights the synergy between macrocyclic design, cryo-EM, and computational modeling to address longstanding obstacles in ion channel drug discovery. JDIC-127 serves as a proof-of-concept for the application of macrocyclization in ion channel pharmacology, offering a roadmap for developing innovative therapeutics targeting TRP channels and beyond, with implications for a wide range of diseases.

PubMed: 41584354
DOI: 10.1016/j.apsb.2025.10.028

Experimental method

ELECTRON MICROSCOPY (3.09 Å)