TRPA1 ankyrin repeat six interacts with a small molecule inhibitor chemotype | Zendy

Wei Chou Tseng | Zendy; David C. Pryde | Zendy; Katrina Yoger | Zendy; Karen Padilla | Zendy; Brett M. Antonio | Zendy; Seungil Han | Zendy; Veerabahu Shanmugasundaram | Zendy; Aaron C. Gerlach | Zendy

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TRPA1 ankyrin repeat six interacts with a small molecule inhibitor chemotype

Author(s) -

Wei Chou Tseng,

David C. Pryde,

Katrina Yoger,

Karen Padilla,

Brett M. Antonio,

Seungil Han,

Veerabahu Shanmugasundaram,

Aaron C. Gerlach

Publication year - 2018

Publication title -

proceedings of the national academy of sciences

Language(s) - English

Resource type - Journals

eISSN - 1091-6490

pISSN - 0027-8424

DOI - 10.1073/pnas.1808142115

Subject(s) - small molecule , transient receptor potential channel , mutagenesis , chemistry , amino acid , drug discovery , transmembrane domain , ankyrin repeat , pharmacology , biochemistry , lipophilicity , drug development , stereochemistry , drug , biology , receptor , mutation , gene

Significance TRPA1 channels are expressed primarily in sensory neurons with human genetic linkage to pain disorders. Despite the strong confidence for TRPA1 as a therapeutic target, few modulators have advanced to the clinic being hindered by poor physiochemical properties and narrow structure-activity relationships related to their site of interaction. We report the discovery of a potent and selective thiadiazole small molecule class of TRPA1 inhibitor that interacts with the N-terminal ankyrin repeat (ankyrinR) domain. The discovery of this interaction site provides opportunities to broaden TRPA1 small molecule drug discovery for the treatment of pain and adds insight into TRPA1 channel gating mechanisms.

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