{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,14]],"date-time":"2026-08-14T20:50:37Z","timestamp":1786740637963,"version":"build-2736575974"},"reference-count":50,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2024,6,25]],"date-time":"2024-06-25T00:00:00Z","timestamp":1719273600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J of Molecular Recognition"],"published-print":{"date-parts":[[2024,9]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Doxepin is an antihistamine and tricyclic antidepressant that binds to the histamine H<jats:sub>1<\/jats:sub> receptor (H<jats:sub>1<\/jats:sub>R) with high affinity. Doxepin is an 85:15 mixture of the E\u2010 and Z\u2010isomers. The Z\u2010isomer is well known to be more effective than the E\u2010isomer, whereas based on the crystal structure of the H<jats:sub>1<\/jats:sub>R\/doxepin complex, the hydroxyl group of Thr112<jats:sup>3.37<\/jats:sup> is close enough to form a hydrogen bond with the oxygen atom of the E\u2010isomer. The detailed binding characteristics and reasons for the differences remain unclear. In this study, we analyzed doxepin isomers bound to the receptor following extraction from a purified H<jats:sub>1<\/jats:sub>R protein complexed with doxepin. The ratio of the E\u2010 and Z\u2010isomers bound to wild\u2010type (WT) H<jats:sub>1<\/jats:sub>R was 55:45, indicating that the Z\u2010isomer was bound to WT H<jats:sub>1<\/jats:sub>R with an approximately 5.2\u2010fold higher affinity than the E\u2010isomer. For the T112<jats:sup>3.37<\/jats:sup>V mutant, the E\/Z ratio was 89:11, indicating that both isomers have similar affinities. Free energy calculations using molecular dynamics (MD) simulations also reproduced the experimental results of the relative binding free energy differences between the isomers for WT and T112<jats:sup>3.37<\/jats:sup>V. Furthermore, MD simulations revealed that the hydroxyl group of T112<jats:sup>3.37<\/jats:sup> did not form hydrogen bonds with the E\u2010isomer, but with the adjacent residues in the binding pocket. Analysis of the receptor\u2010bound doxepin and MD simulations suggested that the hydroxyl group of T112<jats:sup>3.37<\/jats:sup> contributes to the formation of a chemical environment in the binding pocket, which is slightly more favorable for the Z\u2010isomer without hydrogen bonding with doxepin.<\/jats:p>","DOI":"10.1002\/jmr.3098","type":"journal-article","created":{"date-parts":[[2024,6,26]],"date-time":"2024-06-26T01:20:23Z","timestamp":1719364823000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Binding characteristics of the doxepin E\/Z\u2010isomers to the histamine <scp>H<sub>1<\/sub><\/scp> receptor revealed by receptor\u2010bound ligand analysis and molecular dynamics study"],"prefix":"10.1002","volume":"37","author":[{"given":"Hiroto","family":"Kaneko","sequence":"first","affiliation":[{"name":"Department of Biological Science and Technology Tokyo University of Science  Tokyo 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