{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T01:44:02Z","timestamp":1791855842760,"version":"4.3.4"},"reference-count":114,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2025,5,26]],"date-time":"2025-05-26T00:00:00Z","timestamp":1748217600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Background\/Objectives: Highly pathogenic coronaviruses (CoVs), including SARS-CoV, MERS-CoV, and SARS-CoV-2, continue to pose a significant threat to global public health. Therefore, this situation highlights the urgent need for effective broad-spectrum antiviral agents. Curcumin, a naturally occurring polyphenol known for its antiviral and anti-inflammatory properties, faces limitations such as poor bioavailability and rapid metabolic degradation, restricting its practical therapeutic application. Methods: To address these limitations, this study introduces a novel design strategy aimed at 42 new curcumin derivatives with improved pharmacokinetic profiles, specifically targeting the conserved coronavirus enzyme papain-like protease (PLpro). A comprehensive in silico evaluation was performed, including ADMET (Absorption, Distribution, Metabolism, Elimination, and Toxicity) analysis, molecular docking, molecular dynamics (MD) simulations, and Molecular Mechanics\/Poisson-Boltzmann Surface Area (MM\/PBSA) calculations. Results: Extensive pharmacokinetic and toxicological assessments (ADMET analyses) identified 19 derivatives exhibiting optimal drug-like characteristics according to Lipinski\u2019s Rule of Five (Ro5). Molecular docking analyses demonstrated that these novel derivatives possess significantly enhanced binding affinities to PLpro enzymes from SARS-CoV, MERS-CoV, and SARS-CoV-2 compared to standard antiviral agents and natural curcumin. Further validation through MD simulations and MM\/PBSA calculations confirmed the structural stability and robust interactions of the most promising derivatives within the SARS-CoV PLpro active site. Conclusions: The results of this study provide essential structural and functional insights, reinforcing the potential of these newly developed curcumin derivatives as potent, broad-spectrum antiviral agents effective against current and future coronavirus threats.<\/jats:p>","DOI":"10.3390\/ph18060798","type":"journal-article","created":{"date-parts":[[2025,5,29]],"date-time":"2025-05-29T04:46:38Z","timestamp":1748493998000},"page":"798","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Structure-Based Design and In-Silico Evaluation of Computationally Proposed Curcumin Derivatives as Potential Inhibitors of the Coronaviral PLpro Enzymes"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5105-8331","authenticated-orcid":false,"given":"Hakan","family":"Alici","sequence":"first","affiliation":[{"name":"Department of Physics, Faculty of Science, Zonguldak B\u00fclent Ecevit University, 67100 Zonguldak, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,5,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1038\/s41579-018-0118-9","article-title":"Origin and evolution of pathogenic coronaviruses","volume":"17","author":"Cui","year":"2019","journal-title":"Nat. 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