{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T19:47:42Z","timestamp":1791229662919,"version":"4.1.0"},"reference-count":38,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2026,7,2]],"date-time":"2026-07-02T00:00:00Z","timestamp":1782950400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"University of Medicine and Pharmacy of Craiova, Romania"},{"id":[{"id":"https:\/\/ror.org\/031d5vw30","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Life"],"abstract":"<jats:p>Combination analgesic therapy is commonly used to improve pain control, yet conventional molecular docking approaches typically evaluate individual ligands and provide limited insight into potential intermolecular associations between co-administered drugs. In this study, paracetamol, codeine, and their proposed 1:1 and 2:1 non-covalent assemblies were investigated using lipophilicity analysis, molecular docking, short molecular dynamics relaxation, electrostatic potential surface mapping, and HOMO\u2013LUMO analysis. Docking simulations were performed against cyclooxygenase-1 (COX-1), cyclooxygenase-2 (COX-2), and the \u03bc-opioid receptor (MOR). The proposed assemblies produced docking scores that differed from those of the individual compounds, with the most pronounced differences observed for the cyclooxygenase targets. The 2:1 assemblies generally exhibited the most favorable docking scores, whereas the predicted interaction profiles at MOR appeared to be more dependent on molecular orientation. Molecular dynamics relaxation and electronic structure analyses further revealed differences in the energetic and electronic characteristics of the investigated configurations. These findings support the theoretical feasibility of distinct interaction patterns among the proposed paracetamol\u2013codeine assemblies within the applied computational framework. However, the reported docking scores represent relative computational values rather than experimentally validated binding affinities, and the short-timescale molecular dynamics simulations provide only preliminary information regarding conformational stability. Furthermore, the existence and biological relevance of the proposed assemblies under physiological conditions remain to be established. This study provides a computational basis for future investigations of intermolecular associations in multicomponent drug systems.<\/jats:p>","DOI":"10.3390\/life16071104","type":"journal-article","created":{"date-parts":[[2026,7,2]],"date-time":"2026-07-02T10:04:44Z","timestamp":1782986684000},"page":"1104","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Computational Insights into the Molecular Synergy of Paracetamol and Codeine"],"prefix":"10.3390","volume":"16","author":[{"given":"Manuel-Ovidiu","family":"Amzoiu","sequence":"first","affiliation":[{"name":"Faculty of Pharmacy, University of Medicine and Pharmacy of Craiova, 200638 Craiova, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Georgeta Sofia","family":"Popescu","sequence":"additional","affiliation":[{"name":"Faculty of Food Eng, University of Life Science \u201cKing Michael\u201d from Timisoara, 300645 Timisoara, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-1659-0942","authenticated-orcid":false,"given":"Denisa Constantina","family":"Amzoiu","sequence":"additional","affiliation":[{"name":"Faculty of Pharmacy, University of Medicine and Pharmacy of Craiova, 200638 Craiova, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Viorica","family":"Cioc\u00eelteu","sequence":"additional","affiliation":[{"name":"Faculty of Pharmacy, University of Medicine and Pharmacy of Craiova, 200638 Craiova, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriela","family":"Rau","sequence":"additional","affiliation":[{"name":"Faculty of Pharmacy, University of Medicine and Pharmacy of Craiova, 200638 Craiova, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4261-1497","authenticated-orcid":false,"given":"Costel Valentin","family":"Manda","sequence":"additional","affiliation":[{"name":"Faculty of Pharmacy, University of Medicine and Pharmacy of Craiova, 200638 Craiova, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrei","family":"Gresita","sequence":"additional","affiliation":[{"name":"Department of Physiology, Faculty of Medicine, University of Medicine and Pharmacy of Craiova, 200638 Craiova, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oana","family":"Taisescu","sequence":"additional","affiliation":[{"name":"Department of Anatomy, Faculty of Medicine, University of Medicine and Pharmacy of Craiova, 200638 Craiova, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,2]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"106388","DOI":"10.1016\/j.envint.2021.106388","article-title":"Acetaminophen metabolism revisited using non-targeted analyses: Implications for human biomonitoring","volume":"149","author":"David","year":"2021","journal-title":"Environ. 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