{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,4]],"date-time":"2025-12-04T14:43:47Z","timestamp":1764859427039,"version":"build-2065373602"},"reference-count":32,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2022,5,6]],"date-time":"2022-05-06T00:00:00Z","timestamp":1651795200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>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 (\u0394G) 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 \u03c0-\u03c0 with Phe556, and a cation-\u03c0 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.<\/jats:p>","DOI":"10.3390\/molecules27092977","type":"journal-article","created":{"date-parts":[[2022,5,8]],"date-time":"2022-05-08T21:31:20Z","timestamp":1652045480000},"page":"2977","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Allosteric Binding of MDMA to the Human Serotonin Transporter (hSERT) via Ensemble Binding Space Analysis with \u0394G Calculations, Induced Fit Docking and Monte Carlo Simulations"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6322-1295","authenticated-orcid":false,"given":"\u00c1ngel A.","family":"Islas","sequence":"first","affiliation":[{"name":"Vicerrector\u00eda de Investigaci\u00f3n y Estudios de Posgrado, Benem\u00e9rita Universidad Aut\u00f3noma de Puebla, Puebla 72592, Mexico"},{"name":"Laboratory of Computational Molecular Simulations, Departamento de Farmacia, Benem\u00e9rita Universidad Aut\u00f3noma de Puebla, Puebla 72592, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2196-2682","authenticated-orcid":false,"given":"Thomas","family":"Scior","sequence":"additional","affiliation":[{"name":"Laboratory of Computational Molecular Simulations, Departamento de Farmacia, Benem\u00e9rita Universidad Aut\u00f3noma de Puebla, Puebla 72592, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,5,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"3036","DOI":"10.1021\/acs.jmedchem.8b01925","article-title":"Electrostatic Complementarity as a Fast and Effective Tool to Optimize Binding and Selectivity of Protein\u2013Ligand Complexes","volume":"62","author":"Bauer","year":"2019","journal-title":"J. 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