{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T01:35:46Z","timestamp":1790472946532,"version":"4.1.0"},"reference-count":44,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2022,1,21]],"date-time":"2022-01-21T00:00:00Z","timestamp":1642723200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>A drug\/proton-antiporter, whose the molecular structure is still unknown, was previously evidenced at the blood-brain barrier (BBB) by functional experiments. The computational method could help in the identification of substrates of this solute carrier (SLC) transporter. Two pharmacophore models for substrates of this transporter using the FLAPpharm approach were developed. The trans-stimulation potency of 40 selected compounds for already known specific substrates ([3H]-clonidine) were determined and compared in the human brain endothelial cell line hCMEC\/D3. Results. The two pharmacophore models obtained were used as templates to screen xenobiotic and endogenous compounds from four databases (e.g., Specs), and 45 hypothetical new candidates were tested to determine their substrate capacity. Psychoactive drugs such as antidepressants (e.g., imipramine, desipramine), antipsychotics\/neuroleptics such as phenothiazine derivatives (chlorpromazine), sedatives anti-histamine-H1 drugs (promazine, promethazine, triprolidine, pheniramine), opiates\/opioids (e.g., hydrocodone), trihexyphenidyl and sibutramine were correctly predicted as proton-antiporter substrates. The best performing pharmacophore model for the proton-antiporter substrates appeared as a good predictor of known substrates and allowed the identification of new substrate compounds. This model marks a new step in the characterization of this drug\/proton-antiporter and will be of great use in uncovering its substrates and designing chemical entities with an improved influx capability to cross the BBB.<\/jats:p>","DOI":"10.3390\/pharmaceutics14020255","type":"journal-article","created":{"date-parts":[[2022,1,23]],"date-time":"2022-01-23T20:34:40Z","timestamp":1642970080000},"page":"255","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Pharmacophore-Based Discovery of Substrates of a Novel Drug\/Proton-Antiporter in the Human Brain Endothelial hCMEC\/D3 Cell Line"],"prefix":"10.3390","volume":"14","author":[{"given":"Maria","family":"Smirnova","sequence":"first","affiliation":[{"name":"Universit\u00e9 de Paris, INSERM UMR_S1144, Optimisation Th\u00e9rapeutique en Neuropsychopharmacologie, 75006 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9282-9013","authenticated-orcid":false,"given":"Laura","family":"Goracci","sequence":"additional","affiliation":[{"name":"Biology and Biotechnology, Department of Chemistry, University of Perugia, 06123 Perugia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriele","family":"Cruciani","sequence":"additional","affiliation":[{"name":"Biology and Biotechnology, Department of Chemistry, University of Perugia, 06123 Perugia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laetitia","family":"Federici","sequence":"additional","affiliation":[{"name":"Universit\u00e9 de Paris, INSERM UMR_S1144, Optimisation Th\u00e9rapeutique en Neuropsychopharmacologie, 75006 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9526-2294","authenticated-orcid":false,"given":"Xavier","family":"Decl\u00e8ves","sequence":"additional","affiliation":[{"name":"Universit\u00e9 de Paris, INSERM UMR_S1144, Optimisation Th\u00e9rapeutique en Neuropsychopharmacologie, 75006 Paris, France"},{"name":"Biologie du M\u00e9dicament et Toxicologie, AP-HP, H\u00f4pital Cochin, 75014 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"H\u00e9l\u00e8ne","family":"Chapy","sequence":"additional","affiliation":[{"name":"Universit\u00e9 de Paris, INSERM UMR_S1144, Optimisation Th\u00e9rapeutique en Neuropsychopharmacologie, 75006 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8500-3574","authenticated-orcid":false,"given":"Salvatore","family":"Cisternino","sequence":"additional","affiliation":[{"name":"Universit\u00e9 de Paris, INSERM UMR_S1144, Optimisation Th\u00e9rapeutique en Neuropsychopharmacologie, 75006 Paris, France"},{"name":"Service Pharmacie, AP-HP, H\u00f4pital Necker-Enfants Malades, 75015 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,1,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1016\/j.nbd.2009.07.030","article-title":"Structure and function of the blood-brain barrier","volume":"37","author":"Abbott","year":"2010","journal-title":"Neurobiol. 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