Allosteric Binding of MDMA to the Human Serotonin Transporter (hSERT) via Ensemble Binding Space Analysis with ΔG Calculations, Induced Fit Docking and Monte Carlo Simulations.
Molecules (Basel, Switzerland) May 6, 2022 DOI: 10.3390/molecules27092977 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Theoretical or computational modeling study Peer reviewed |
|---|---|
| Topics | MDMA Serotonin |
| Keywords | 3d-rism Cresset Gibbs free energy Nps Xed Antidepressant Bath salts Benzofuran Cathinone Cocaine Designer drugs Electrostatic complementarity Entactogen Escitalopram Methamphetamine Psychoactive |
| Key points | The authors propose a structure-based mechanistic model in which MDMA binds both the central S1 and allosteric S2 sites of the human serotonin transporter, with a favorable dual binding mode at S2 and an internalization pathway through intermediate conformations. Computed binding results correlated with experimental data (r = 0.93 for S1, 0.86 for S2), and MDMA's interactions suggest a distinctive chemotype compared with serotonin and antidepressants. |
Abstract
Despite the recent promising results of MDMA (3,4-methylenedioxy-methamphetamine) as a psychotherapeutic agent and its history of misuse, little is known about its molecular mode of action. MDMA enhances monoaminergic neurotransmission in the brain and its valuable psychoactive effects are associated to a dual action on the 5-HT transporter (SERT). This drug inhibits the reuptake of 5-HT (serotonin) and reverses its flow, acting as a substrate for the SERT, which possesses a central binding site (S1) for antidepressants as well as an allosteric (S2) one. Previously, we characterized the spatial binding requirements for MDMA at S1. Here, we propose a structure-based mechanistic model of MDMA occupation and translocation across both binding sites, applying ensemble binding space analyses, electrostatic complementarity, and Monte Carlo energy perturbation theory. Computed results were correlated with experimental data (r = 0.93 and 0.86 for S1 and S2, respectively). Simulations on all hSERT available structures with Gibbs free energy estimations (ΔG) revealed a favourable and pervasive dual binding mode for MDMA at S2, i.e., adopting either a 5-HT or an escitalopram-like orientation. Intermediate ligand conformations were identified within the allosteric site and between the two sites, outlining an internalization pathway for MDMA. Among the strongest and more frequent interactions were salt bridges with Glu494 and Asp328, a H-bond with Thr497, a π-π with Phe556, and a cation-π with Arg104. Similitudes and differences with the allosteric binding of 5-HT and antidepressants suggest that MDMA may have a distinctive chemotype. Thus, our models may provide a framework for future virtual screening studies and pharmaceutical design and to develop hSERT allosteric compounds with a unique psychoactive MDMA-like profile.