Transient receptor potential ankyrin 1 (TRPA1) is a class of ion channels that have generated broad interest in the pharmaceutical industry for the treatment of both pain and asthma.  Over the past decade, multiple antagonist classes have been reported in the literature with a wide range of structural diversity.  Our work has focused on the development of two series of antagonists: the proline sulfonamides and the hypoxanthines, which have very distinct physicochemical properties and pharmacokinetic (PK) trends.  Structural insights using cryogenic electron microscopy (cryoEM) studies revealed two different binding sites: a membrane-exposed proline sulfonamide transmembrane site and an intracellular hypoxanthine site near the membrane interface.  Herein we present how their distinctive binding sites, and their location relative to the cell membrane, influenced the optimization trajectories and overall drug profiles of each antagonist class.  We also introduce a novel metric, the “membrane ligand efficiency” (MLE), which could provide an additional tool for scientists working in the field.

Drug design at the cell membrane interface: Impact of binding site environment on the optimization of TRPA1 antagonists

Fall 2022 abstracts, posters, and presentations will launch in mid-September.

ACS Fall 2022

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.