Insights into the structure and function of 5-HT2familyserotonin receptors reveal novel strategies for therapeutic target development

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Abstract
5-HT2 family serotonin receptors, principal sites of action of serotonin in the brain, represent major molecular targets for drugs used in treating a variety of diseases including schizophrenia, depression, anxiety, eating disorders, obsessive-compulsive disorder, chronic pain conditions and obesity. The 5-HT2 family of receptors has three members: 5-HT2A, 5-HT2B and 5-HT2C. Therefore, it is likely that subtype-selective compounds will be needed to avoid serious side effects and to enhance therapeutic indices. Unfortunately, recent insights into the structure and function of 5-HT2A receptors have revealed that structurally-diverse agonists and antagonists have distinct modes of interacting with 5-HT2A receptors, complicating efforts at structure-based drug-design. These distinct binding modes would not have been predicted based on conventional structure-activity relationships or static docking models. Fortunately, these complicated binding modes can be predicted and simulated using molecular dynamics, all...