4192023

Targeting a hidden conformation to design safer psychedelic therapies

Date
March 23, 2025

Achieving selectivity between closely related receptors is a longstanding challenge in drug design. Psychedelics, which show great promise in treating mental health and substance use disorders, work by activating the serotonin 2A receptor (5HT2A), but they also activate the closely related serotonin 2B receptor (5HT2B), which is known to cause heart valve disease. Because the binding pockets of 5HT2A and 5HT2B are almost identical, achieving selectivity for 5HT2A has proven challenging. Using molecular dynamics simulations, we discovered a "hidden" conformation adopted by 5HT2A but not by 5HT2B. Targeting this conformation enabled us to design several ligands that activate 5HT2A but not 5HT2B. The designed ligands exert long-lasting antidepressant-like action in mice. In addition to advancing the development of safer drugs to treat mental health and substance use disorders, our results demonstrate the feasibility of targeting computationally discovered receptor conformations to design selective drugs.

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