Research

Functional selectivity (i.e., biased agonism) in GPCRs is a promising concept to potentially attain better therapeutic outcomes since there have been a few successful development of G protein vs. β arrestin biased ligands in humans. However, G protein subtype functional selectivity has been largely unexplored despite its great potential in achieving cell-type specific pharmacology. We have successfully demonstrated it between G_αs and G_αolf (G_s/olf) with the dopamine D1 receptor in the neurological therapeutic context. We are furthering this work in G_s/olf as well as other G protein subtypes to establish applicability of G protein subtype functional selectivity.

Targeting Allosteric Sites

Allosteric binding sites are often quite divergent even among receptors that bind to a same neuromodulator, offering opportunities for receptor selectivity and unique pharmacological behaviors. Within dopamine D2 and D3 receptor pharmacology, we have characterized bitopic ligands that bind both orthosteric and allosteric binding sites, which provided spatial understanding of allosteric site and space that connect the two sites. Working closely with collaborators, we try to understand allosteric sites better and develop pharmacology targeting them in the forms of allosteric modulators or bitopic ligands.

Mechanisms of Superagonism

Synthetic cannabinoid receptor agonists (SCRAs) remain a significant public health problem and are particularly remarkable as many of them elicit efficacies significantly higher than a reference full agonist at CB1. We study the molecular underpinnings of superagonism as well as acute toxicity at the physiological levels. We have already found that a subtle change in SCRA structure makes a tight pocket interaction, resulting in superagonism. Our lab is dedicated to study molecular mechanisms of substance use disorders (SUDs) as 48.7 million people are considered to have an SUD in 2022 according to the U.S. Department of Health and Human Services.