{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,20]],"date-time":"2026-05-20T21:29:01Z","timestamp":1779312541837,"version":"3.51.4"},"reference-count":37,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2025,8,25]],"date-time":"2025-08-25T00:00:00Z","timestamp":1756080000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["analyticalsciencejournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Drug Development Research"],"published-print":{"date-parts":[[2025,9]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:p>Botulinum neurotoxins are the most potent toxins responsible for causing flaccid paralysis of muscles by blocking the release of acetylcholine at the neuromuscular junction. There are no postexposure therapeutics and effective active\/passive prophylaxis available for the treatment. Therefore, it is highly desirable to develop a potential antidote to counter botulinum neurotoxicity. In this study, ~800 molecules were mined by a structure similarity search from open databases and docked into the pocket of the catalytic domain of botulinum toxin type E using AutoDock 4.2. Twenty\u2010four small molecules with the best scoring function were selected and evaluated using in vitro and in vivo assays. Among these, two molecules, NSC1011 and NSC1012, were identified as inhibiting the catalytic activity of BoNT\/E, with IC<jats:sub>50<\/jats:sub> values of 31.25\u2009\u00b1\u20091.0\u2009\u03bcM and 55.45\u2009\u00b1\u20095.2\u2009\u03bcM and <jats:italic>K<\/jats:italic><jats:sub>D<\/jats:sub> of 5.54E\u221207 and 6.51E\u221206\u2009M, respectively. To find inhibitors that can reverse the neurotoxicity more effectively, we have derived and synthesized 12 analogs of NSC1011. These compounds showed higher inhibition than the parent molecules, with IC<jats:sub>50<\/jats:sub> and <jats:italic>K<\/jats:italic><jats:sub>D<\/jats:sub> values of 4.375\u2009\u00b1\u20092.3\u2009\u00b5M and 1.61E\u221208\u2009M (C25.12) and 10.25\u2009\u00b1\u20093.0\u2009\u00b5M and 4.70E\u201008\u2009M (C25.9). Compounds C25.9 and C25.12 completely protected mice in premixed doses and led to significant extension in survival of up to 60\u2009h with therapeutic treatment. This study showed that these 8\u2010HQ derivatives had the potency to inhibit BoNT\/E by interacting with the active site. Further studies could lead to the development of undiscovered postexposure therapeutics against this deadly neurotoxin.<\/jats:p>","DOI":"10.1002\/ddr.70148","type":"journal-article","created":{"date-parts":[[2025,8,25]],"date-time":"2025-08-25T10:18:30Z","timestamp":1756117110000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Targeting the Enzymatic Site of Botulinum Neurotoxin Type E With 8\u2010Hydroxyquinolinol\u2013Based Inhibitors: In Silico, In Vitro, and In Vivo Evaluation"],"prefix":"10.1002","volume":"86","author":[{"given":"Priyanka","family":"Sonkar","sequence":"first","affiliation":[{"name":"Biotechnology Division Defence Research and Development Establishment Gwalior MP India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vinita Chauhan","family":"Kushwah","sequence":"additional","affiliation":[{"name":"Biotechnology Division Defence Research and Development Establishment Gwalior MP India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Surabhi","family":"Agnihotri","sequence":"additional","affiliation":[{"name":"Biotechnology Division Defence Research and Development Establishment Gwalior MP India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Deeksha","family":"Disoriya","sequence":"additional","affiliation":[{"name":"Biotechnology Division Defence Research and Development Establishment Gwalior MP India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Manorama","family":"Vimal","sequence":"additional","affiliation":[{"name":"Test &amp; Evaluation Division Defence Research and Development Establishment Gwalior MP India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3106-9994","authenticated-orcid":false,"given":"Ram Kumar","family":"Dhaked","sequence":"additional","affiliation":[{"name":"Biotechnology Division Defence Research and Development Establishment Gwalior MP India"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2025,8,25]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1021\/bi036278"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M803756200"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00044-024-03272-6"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1021\/jm0300680"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.285.8.1059"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/B978-0-12-374194-3.00020-2"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmc.2004.03.006"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.6b01393"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2003.08.112"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/s0300-9084(00)01173-1"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1021\/jm4012164"},{"issue":"6","key":"e_1_2_11_13_1","first-page":"1","article-title":"Botulinum Toxin Products Overview","volume":"13","author":"Carruthers A.","year":"2008","journal-title":"Skin Therapy Letter"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.2174\/1389557519666190906120228"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bioorg.2019.103297"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.toxicon.2022.106981"},{"key":"e_1_2_11_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cps.2016.03.003"},{"key":"e_1_2_11_18_1","doi-asserted-by":"publisher","DOI":"10.3109\/15563650.2010.526943"},{"key":"e_1_2_11_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.toxicon.2017.06.016"},{"key":"e_1_2_11_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/s0041-0101(01)00157-x"},{"issue":"1","key":"e_1_2_11_21_1","first-page":"30","article-title":"Botulin Toxin: A Weapon in Terrorism","volume":"17","author":"Josko D.","year":"2004","journal-title":"Clinical Laboratory Science"},{"key":"e_1_2_11_22_1","doi-asserted-by":"publisher","DOI":"10.1590\/S0103-50531999000100008"},{"key":"e_1_2_11_23_1","doi-asserted-by":"publisher","DOI":"10.1039\/c2cc17158a"},{"key":"e_1_2_11_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmc.2016.06.036"},{"key":"e_1_2_11_25_1","doi-asserted-by":"publisher","DOI":"10.1107\/S0907444912003551"},{"key":"e_1_2_11_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmb.2008.12.027"},{"key":"e_1_2_11_27_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.abb.2009.09.008"},{"key":"e_1_2_11_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmc.2015.11.043"},{"key":"e_1_2_11_29_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.toxicon.2015.02.012"},{"key":"e_1_2_11_30_1","doi-asserted-by":"publisher","DOI":"10.3390\/bios7030032"},{"key":"e_1_2_11_31_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0065-2911(09)05503-9"},{"key":"e_1_2_11_32_1","doi-asserted-by":"publisher","DOI":"10.1021\/cr50008a003"},{"key":"e_1_2_11_33_1","doi-asserted-by":"publisher","DOI":"10.1124\/pr.116.012658"},{"key":"e_1_2_11_34_1","volume-title":"Proceedings of the 43rd Interagency Botulism Research Coordinating Committee (IBRCC) Meeting","author":"Primak Y.","year":"2006"},{"key":"e_1_2_11_35_1","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.2000.80.2.717"},{"key":"e_1_2_11_36_1","doi-asserted-by":"publisher","DOI":"10.1016\/s0014-5793(98)01041-2"},{"key":"e_1_2_11_37_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-020-70929-8"},{"key":"e_1_2_11_38_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmc.2016.07.031"}],"container-title":["Drug Development Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/analyticalsciencejournals.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/ddr.70148","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,13]],"date-time":"2025-10-13T21:10:57Z","timestamp":1760389857000},"score":1,"resource":{"primary":{"URL":"https:\/\/analyticalsciencejournals.onlinelibrary.wiley.com\/doi\/10.1002\/ddr.70148"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,8,25]]},"references-count":37,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2025,9]]}},"alternative-id":["10.1002\/ddr.70148"],"URL":"https:\/\/doi.org\/10.1002\/ddr.70148","archive":["Portico"],"relation":{},"ISSN":["0272-4391","1098-2299"],"issn-type":[{"value":"0272-4391","type":"print"},{"value":"1098-2299","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,8,25]]},"assertion":[{"value":"2025-05-02","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-08-10","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-08-25","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70148"}}