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This toxicity is a major concern associated with the widespread use of ApAP, a commonly used nonsteroidal anti\u2010inflammatory drug. To address this important issue, a series of novel nonopioid analgesic candidates with reduced toxicity have been recently reported. However, the molecular and atomic\u2010level mechanisms underlying their decreased toxicity remain largely unexplored. In this study, computational analyses\u00a0is\u00a0performed to investigate the dynamic behavior, physicochemical properties, and ligand\u2010receptor interactions of these new chemical entities (NCEs). The findings provide a rational explanation for their differing toxicity profiles and contribute to a deeper understanding of their metabolic pathways. Based on these insights, compound\n                    <jats:bold>6<\/jats:bold>\n                    has emerged as a promising ApAP alternative and is currently under development. These investigations pave the way for designing novel hepatotoxicity\u2010free NCE analgesics with improved drug metabolism and pharmacokinetic properties.\n                  <\/jats:p>","DOI":"10.1002\/cmdc.202500639","type":"journal-article","created":{"date-parts":[[2025,10,21]],"date-time":"2025-10-21T22:29:01Z","timestamp":1761085741000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Computational Insights into the Structural Basis for Reduced Hepatotoxicity of Novel Nonopioid Analgesics"],"prefix":"10.1002","volume":"20","author":[{"given":"Claire","family":"Coderch","sequence":"first","affiliation":[{"name":"Departamento de Qu\u00edmica y Bioqu\u00edmica Facultad de Farmacia Universidad San Pablo\u2010CEU CEU Universities  Urbanizaci\u00f3n Montepr\u00edncipe 28668 Madrid Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hernan A.","family":"Baz\u00e1n","sequence":"additional","affiliation":[{"name":"Division of Vascular and Endovascular Surgery Sutter Health, California Pacific Medical Center  San Francisco CA 94109 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nicolas G.","family":"Bazan","sequence":"additional","affiliation":[{"name":"Neuroscience Center of Excellence School of Medicine Louisiana State University Health New Orleans  New Orleans LA 70112 USA"},{"name":"Department of Physiology School of Medicine Louisiana State University Health New Orleans  New Orleans LA 70112 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bhattacharjee","family":"Surjyadipta","sequence":"additional","affiliation":[{"name":"Neuroscience Center of Excellence School of Medicine Louisiana State University Health New Orleans  New Orleans LA 70112 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Julio","family":"Alvarez\u2010Builla","sequence":"additional","affiliation":[{"name":"Department of Organic Chemistry University of Alcala  Alcala de Henares 28871 Madrid Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1101-0373","authenticated-orcid":false,"given":"Beatriz","family":"de Pascual\u2010Teresa","sequence":"additional","affiliation":[{"name":"Departamento de Qu\u00edmica y Bioqu\u00edmica Facultad de Farmacia Universidad San Pablo\u2010CEU CEU Universities  Urbanizaci\u00f3n Montepr\u00edncipe 28668 Madrid Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2025,10,21]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejpain.2005.06.009"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2017.16190"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1097\/j.pain.0000000000003406"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.chemrestox.7b00024"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.phrs.2016.02.020"},{"key":"e_1_2_8_7_1","first-page":"31","volume":"92","author":"Drahl C.","year":"2014","journal-title":"Chem. 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