Peeters Jordy, De Bundel Dimitri, Vanommeslaeghe Kenno
Department of Analytical Chemistry, Applied Chemometrics and Molecular Modelling (FABI), Vrije Universiteit Brussel (VUB), Brussels, Belgium.
Experimental Pharmacology (EFAR) group, Vrije Universiteit Brussel (VUB), Brussels, Belgium.
PLoS Comput Biol. 2025 Sep 3;21(9):e1013000. doi: 10.1371/journal.pcbi.1013000. eCollection 2025 Sep.
The serotonin-2A receptor (5-HT2AR) 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-HT2AR bound with two antipsychotics, three different potential non-hallucinogens and two hallucinogens to identify the receptor's ligand dependent conformations. Overall, our findings suggest that modest 5-HT2AR 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.
在抗抑郁药物领域，5-羟色胺2A受体（5-HT2AR）是药物设计的一个有趣靶点，这类药物可能起效迅速，且/或对难治性病例有效。然而，主要挑战在于该受体的激活会引发幻觉。最近的研究表明，用某些（部分）激动剂激活该受体可能会产生抗抑郁作用而无致幻副作用。尽管该领域已开展了大量研究，但5-羟色胺2A受体这种差异激活的原子细节仍未完全明确。在本研究中，我们对与两种抗精神病药物、三种不同潜在非致幻剂和两种致幻剂结合的5-HT2AR进行了多次原子分子动力学（MD）模拟，以确定受体的配体依赖性构象。总体而言，我们的研究结果表明，适度的5-HT2AR激活只会产生抗抑郁作用，而幻觉是由过度激活导致的。虽然由于存在滥用可能性以及可能狭窄且依赖患者的治疗窗效应，通过微剂量进行适度激活可能存在问题，但通过给予足够弱的部分激动剂进行适度激活可能提供一条可行的药物开发途径。
