Molecular dynamics study of differential effects of serotonin-2A-receptor (5-HT2AR) modulators

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Abstract
The serotonin-2A receptor (5-HT 2A R) is an interesting target for drug design in the context of antidepressants that might have a rapid onset of action and/or be effective in treatment-resistant cases. The main challenge, however, is that the activation of this receptor can provoke hallucinations. Recent studies have shown that activating the receptor with certain (partial) agonists could potentially give rise to antidepressant effect without hallucinogenic side effects. Although substantial research has been done in this area, the atomistic details of this differential activation of the serotonin-2A receptor are not fully understood. In the present study we performed multiple atomistic molecular dynamics (MD) simulations on 5-HT 2A R bound with an antipsychotic, two different potential non-hallucinogenic antidepressants and a hallucinogen to identify the receptor’s ligand dependent conformations. Overall, our findings suggest that modest 5-HT 2A R activation would only yield antidepressant effects and hallucinations result from excessive activation. While modest activation through microdosing may be problematic on account of abuse potential as well as possibly narrow and patient-dependent therapeutic windows, modest activation through administration of a sufficiently weak partial agonist may offer a viable drug development pathway. Author Summary: Activating the serotonin-2A receptor (5-HT2AR) with specific agonists is a promising strategy for the development of a new class of antidepressants. However, potent agonists such as LSD, DMT or psylocibin generally cause hallucinations. To aid the development of 5-HT2AR-targeted antidepressants that do not cause this side effect, we seek to gain a better understanding of the receptor by studying its activation mechanism. Specifically, we performed molecular dynamics simulations to explore how different drugs interact with 5-HT2AR, both in the absence and presence of an intracellular binding partner. This led to the identification of tentative intermediate states along the activation pathway, which could be linked to the ligands’ pharmacological properties. Our findings suggest that hallucinogens cause an excessive build-up of activated receptors, whereas carefully designed mild activators could lead to a new generation of antidepressants that do not induce hallucinations.
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