{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,22]],"date-time":"2025-10-22T20:22:53Z","timestamp":1761164573871,"version":"build-2065373602"},"reference-count":52,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2025,2,18]],"date-time":"2025-02-18T00:00:00Z","timestamp":1739836800000},"content-version":"vor","delay-in-days":17,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100010582","name":"National Computational Infrastructure","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100010582","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Journal of Neurochemistry"],"published-print":{"date-parts":[[2025,2]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Neuronal nicotinic acetylcholine receptors (nAChRs) have an established role in pain pathways and devastating neurodegenerative diseases; however, few drugs have been successfully developed to target them. The most abundant nAChR in the brain, the \u03b14\u03b22 nAChR, is assembled from five subunits in a 3\u03b1:2\u03b2 stoichiometry\u2014(\u03b14)\n                    <jats:sub>3<\/jats:sub>\n                    (\u03b22)\n                    <jats:sub>2<\/jats:sub>\n                    . This receptor contains a unique agonist\u2010binding site at the \u03b14\u03b14 interface in addition to two classical agonist\u2010binding sites at \u03b14\u03b22 interfaces. Most known agonists target both \u03b14\u03b14 and \u03b14\u03b22 sites, however, a few compounds with selectivity for the \u03b14\u03b14 site have been identified. These \u03b14\u03b14 selective compounds have a modulator\u2010like effect akin to benzodiazepines in the \u03b3\u2010aminobutyric acid type A receptor, which is desirable from a drug development perspective. The two most well characterised \u03b14\u03b14 selective compounds are CMPI and NS9283. Both are structurally very different from classical agonists, and it is puzzling how they occupy the same binding site. In the search for a common pharmacophore, we conducted extensive molecular dynamics simulations with both classical agonists and site\u2010selective non\u2010classical compounds. Analyses of the simulations revealed that the \u03b14\u03b14 binding site contains a unique pocket not found in the \u03b14\u03b22 binding site. CMPI and NS9283 were observed to bind in this pocket, thereby explaining why they are selective for the \u03b14\u03b14 binding site. The proposed binding mode featured a closed\u2010loop C conformation, which is strongly correlated with agonism in nAChRs and explained key site\u2010directed mutagenesis data for both compounds. Based on this binding mode, we proposed a pharmacophore for drugs targeting the \u03b14\u03b14 binding site. The proposed pharmacophore captures the essence of the original model, that is, nicotinic agonists act as a bridge between protein subunits. The pharmacophore model we propose is unique to the \u03b14\u03b14 binding site and provides a template for developing new site\u2010selective therapeutic agents.\n                    <jats:boxed-text content-type=\"graphic\" position=\"anchor\">\n                      <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/jnc70000-fig-0008-m.png\">\n                        <jats:alt-text>image<\/jats:alt-text>\n                      <\/jats:graphic>\n                    <\/jats:boxed-text>\n                  <\/jats:p>","DOI":"10.1111\/jnc.70000","type":"journal-article","created":{"date-parts":[[2025,2,19]],"date-time":"2025-02-19T01:55:36Z","timestamp":1739930136000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A Pharmacophore for Drugs Targeting the \u03b14\u03b14 Binding Site of the (\u03b14)\n                    <sub>3<\/sub>\n                    (\u03b22)\n                    <sub>2<\/sub>\n                    Nicotinic Acetylcholine Receptor"],"prefix":"10.1111","volume":"169","author":[{"given":"Ali S.","family":"Kusay","sequence":"first","affiliation":[{"name":"Sydney Pharmacy School, Faculty of Medicine and Health The University of Sydney  Sydney New South Wales Australia"},{"name":"Brain and Mind Centre The University of Sydney  Sydney New South Wales Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yujia","family":"Luo","sequence":"additional","affiliation":[{"name":"Sydney Pharmacy School, Faculty of Medicine and Health The University of Sydney  Sydney New South Wales Australia"},{"name":"Brain and Mind Centre The University of Sydney  Sydney New South Wales Australia"},{"name":"Department of Painology, The First Affiliated Hospital Zhejiang University School of Medicine  Hangzhou China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Megan L.","family":"O'Mara","sequence":"additional","affiliation":[{"name":"Research School of Chemistry The Australian National University  Canberra Australian Capital Territory Australia"},{"name":"Australian Institute for Bioengineering and Nanotechnology The University of Queensland  St Lucia Queensland Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0233-8350","authenticated-orcid":false,"given":"Thomas","family":"Balle","sequence":"additional","affiliation":[{"name":"Sydney Pharmacy School, Faculty of Medicine and Health The University of Sydney  Sydney New South Wales Australia"},{"name":"Brain and Mind Centre The University of Sydney  Sydney New South Wales Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2025,2,18]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.softx.2015.06.001"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuropharm.2014.12.035"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmcl.2008.08.080"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1021\/jm058058h"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/228917a0"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-94-015-7658-1_21"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/0010-4655(95)00042-E"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1007140107"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnmol.2022.886729"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.pa.19.040179.002531"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuropharm.2005.11.026"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1521-3773(19990115)38:1\/2<236::AID-ANIE236>3.0.CO;2-M"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M412389200"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.12095"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1747-0285.2007.00483.x"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1124\/mol.116.103341"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.emboj.7600828"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/0263-7855(96)00018-5"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1021\/jm040219e"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bcp.2011.06.044"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.15188"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0022-3565(24)35314-5"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jcim.7b00152"},{"key":"e_1_2_10_25_1","doi-asserted-by":"publisher","DOI":"10.1021\/ct200196m"},{"key":"e_1_2_10_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bpj.2015.08.015"},{"key":"e_1_2_10_27_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcc.21787"},{"key":"e_1_2_10_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuropharm.2008.07.041"},{"key":"e_1_2_10_29_1","doi-asserted-by":"publisher","DOI":"10.1124\/mol.106.023044"},{"key":"e_1_2_10_30_1","doi-asserted-by":"publisher","DOI":"10.1124\/mol.63.2.332"},{"key":"e_1_2_10_31_1","doi-asserted-by":"publisher","DOI":"10.1021\/jm990973d"},{"key":"e_1_2_10_32_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.7716551"},{"key":"e_1_2_10_33_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bcp.2013.07.001"},{"key":"e_1_2_10_34_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.str.2019.04.008"},{"key":"e_1_2_10_35_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M114.568097"},{"key":"e_1_2_10_36_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0091232"},{"key":"e_1_2_10_37_1","doi-asserted-by":"publisher","DOI":"10.1021\/ct100578z"},{"key":"e_1_2_10_38_1","doi-asserted-by":"publisher","DOI":"10.1021\/ct401098b"},{"key":"e_1_2_10_39_1","doi-asserted-by":"publisher","DOI":"10.1021\/ct900487a"},{"key":"e_1_2_10_40_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M111.292243"},{"key":"e_1_2_10_41_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrd3502"},{"key":"e_1_2_10_42_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00249-011-0700-9"},{"key":"e_1_2_10_43_1","doi-asserted-by":"publisher","DOI":"10.1021\/jm050540c"},{"key":"e_1_2_10_44_1","doi-asserted-by":"publisher","DOI":"10.2147\/JPR.S169637"},{"key":"e_1_2_10_45_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1476-5381.2012.01989.x"},{"key":"e_1_2_10_46_1","doi-asserted-by":"publisher","DOI":"10.1021\/jm801400g"},{"key":"e_1_2_10_47_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-018-0081-7"},{"key":"e_1_2_10_48_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41386-019-0475-8"},{"key":"e_1_2_10_49_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M116.771246"},{"key":"e_1_2_10_50_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature07768"},{"key":"e_1_2_10_51_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41422-021-00509-6"},{"key":"e_1_2_10_52_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.95.21.12088"},{"key":"e_1_2_10_53_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bcp.2011.05.007"}],"container-title":["Journal of Neurochemistry"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/jnc.70000","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,21]],"date-time":"2025-10-21T18:21:45Z","timestamp":1761070905000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/jnc.70000"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,2]]},"references-count":52,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2025,2]]}},"alternative-id":["10.1111\/jnc.70000"],"URL":"https:\/\/doi.org\/10.1111\/jnc.70000","archive":["Portico"],"relation":{},"ISSN":["0022-3042","1471-4159"],"issn-type":[{"type":"print","value":"0022-3042"},{"type":"electronic","value":"1471-4159"}],"subject":[],"published":{"date-parts":[[2025,2]]},"assertion":[{"value":"2024-07-24","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-01-06","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-02-18","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70000"}}