Mental health and substance use disorders represent the leading cause of years lost to disability or premature death in the United States. When combined with psychotherapy, psychedelic drugs—such as LSD and “magic mushrooms”, which act as agonists at the serotonin 2A receptor (5-HT2AR)—are proving effective in treating these disorders. However, psychedelic drugs have serious side effects and do not achieve sufficient 5-HT2AR selectivity for widespread clinical use. Thus, there is a "gold rush" of research into the development of novel 5-HT2AR agonists to treat mental health and substance use disorders. Undesired activation of the closely related serotonin 2B receptor (5-HT2BR) is of particular concern because it leads to heart valve disease, and compounds that activate 5-HT2BR cannot be developed clinically. Because the binding pockets of 5-HT2 receptors are essentially identical, it has proven difficult to design selective 5-HT2AR agonists. To understand how to design selective 5-HT2AR agonists, we ran extensive all-atom molecular dynamics (MD) simulations of 5-HT2 receptors. Using mechanistic insights from these simulations, we successfully designed several selective 5-HT2AR agonists. These results serve as a starting point for the development of safer and more effective neuropsychiatric drugs.

Computational design of selective agonists for the serotonin 2A receptor

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