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The activation of V1bR induces the secretion of adrenocorticotropin hormone (ACTH) from the anterior pituitary cells which, in turn, stimulates the production of cortisol via the adrenal cortex. Clinical studies have demonstrated the chronic dysfunction of the HPA axis in patients with several psychiatric disorders. Thus, the inhibition of the V1b receptor and normalizing the HPA axis hyperactivity is a promising approach to the treatment of many stress\u2010related disorders such as anxiety and depression. Nelivaptan is a selective V1bR antagonist that can be used for this purpose and an excellent molecule to study how antagonists interact with V1bR, especially since in recent years the experimental structures of vasopressin V2 and oxytocin receptors were solved, providing high\u2010similarity templates for homology modeling of V1bR. Therefore, in this work, six independent molecular dynamics simulations of a V1bR\u2010nelivaptan complex in a fully hydrated lipid bilayer, yielding a total simulation time of 6.0\u2009\u03bcs, have been conducted. In the lowest\u2010energy complexes obtained in this work and proposed to be the most probable structure of the V1bR\u2010nelivaptan complex, the location of the ligand inside the receptor pocket is very similar to that of the other ligands observed in the experimental structures of the vasopressin\/oxytocin receptor family. The receptor\u2010ligand interaction has been analyzed and described, revealing the details of the molecular mechanism of this antagonist binding to V1bR and a probable contribution of L200\n                    <jats:sup>5\u00d740<\/jats:sup>\n                    and T203\n                    <jats:sup>5\u00d743<\/jats:sup>\n                    to binding selectivity.\n                  <\/jats:p>","DOI":"10.1002\/bip.23627","type":"journal-article","created":{"date-parts":[[2024,9,17]],"date-time":"2024-09-17T14:10:38Z","timestamp":1726582238000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Structural Basis for Antagonist Binding to Vasopressin V1b Receptor Revealed by the Molecular Dynamics Simulations"],"prefix":"10.1002","volume":"116","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9411-4679","authenticated-orcid":false,"given":"Magdalena 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