{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,9]],"date-time":"2026-03-09T04:25:42Z","timestamp":1773030342267,"version":"3.50.1"},"reference-count":53,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2025,7,21]],"date-time":"2025-07-21T00:00:00Z","timestamp":1753056000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["CIMB"],"abstract":"<jats:p>The global impact of the COVID-19 crisis has underscored the need for novel therapeutic candidates capable of efficiently targeting essential viral proteins. Existing therapeutic strategies continue to encounter limitations such as reduced efficacy against emerging variants, safety concerns, and suboptimal pharmacodynamics, which emphasize the potential of natural-origin compounds as supportive agents with immunomodulatory, anti-inflammatory, and antioxidant benefits. The present study significantly advances prior molecular docking research through comprehensive virtual screening of structurally related analogs derived from antiviral phytochemicals. These compounds were evaluated specifically against the SARS-CoV-2 main protease (3CLpro) and papain-like protease (PLpro). Utilizing chemical similarity algorithms via the ChEMBL database, over 600 candidate molecules were retrieved and subjected to automated docking, interaction pattern analysis, and comprehensive ADMET profiling. Several analogs showed enhanced binding scores relative to their parent scaffolds, with CHEMBL1720210 (a shogaol-derived analog) demonstrating strong interaction with PLpro (\u22129.34 kcal\/mol), and CHEMBL1495225 (a 6-gingerol derivative) showing high affinity for 3CLpro (\u22128.04 kcal\/mol). Molecular interaction analysis revealed that CHEMBL1720210 forms hydrogen bonds with key PLpro residues including GLY163, LEU162, GLN269, TYR265, and TYR273, complemented by hydrophobic interactions with TYR268 and PRO248. CHEMBL1495225 establishes multiple hydrogen bonds with the 3CLpro residues ASP197, ARG131, TYR239, LEU272, and GLY195, along with hydrophobic contacts with LEU287. Gene expression predictions via DIGEP-Pred indicated that the top-ranked compounds could influence biological pathways linked to inflammation and oxidative stress, processes implicated in COVID-19\u2019s pathology. Notably, CHEMBL4069090 emerged as a lead compound with favorable drug-likeness and predicted binding to PLpro. Overall, the applied in silico framework facilitated the rational prioritization of bioactive analogs with promising pharmacological profiles, supporting their advancement toward experimental validation and therapeutic exploration against SARS-CoV-2.<\/jats:p>","DOI":"10.3390\/cimb47070577","type":"journal-article","created":{"date-parts":[[2025,7,21]],"date-time":"2025-07-21T17:27:36Z","timestamp":1753118856000},"page":"577","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Computational Evaluation and Multi-Criteria Optimization of Natural Compound Analogs Targeting SARS-CoV-2 Proteases"],"prefix":"10.3390","volume":"47","author":[{"given":"Paul Andrei","family":"Negru","sequence":"first","affiliation":[{"name":"Doctoral School of Biological and Biomedical Sciences, University of Oradea, 410087 Oradea, Romania"},{"name":"Department of Preclinical Disciplines, Faculty of Medicine and Pharmacy, University of Oradea, 410073 Oradea, Romania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7625-8177","authenticated-orcid":false,"given":"Andrei-Flavius","family":"Radu","sequence":"additional","affiliation":[{"name":"Doctoral School of Biological and Biomedical Sciences, University of Oradea, 410087 Oradea, Romania"},{"name":"Department of Psycho-Neurosciences and Recovery, Faculty of Medicine and Pharmacy, University of Oradea, 410073 Oradea, Romania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ada","family":"Radu","sequence":"additional","affiliation":[{"name":"Doctoral School of Biological and Biomedical Sciences, University of Oradea, 410087 Oradea, Romania"},{"name":"Department of Pharmacy, Faculty of Medicine and Pharmacy, University of Oradea, 410028 Oradea, Romania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0296-6592","authenticated-orcid":false,"given":"Delia Mirela","family":"Tit","sequence":"additional","affiliation":[{"name":"Doctoral School of Biological and Biomedical Sciences, University of Oradea, 410087 Oradea, Romania"},{"name":"Department of Pharmacy, Faculty of Medicine and Pharmacy, University of Oradea, 410028 Oradea, Romania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gabriela","family":"Bungau","sequence":"additional","affiliation":[{"name":"Doctoral School of Biological and Biomedical Sciences, University of Oradea, 410087 Oradea, Romania"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,7,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Kabir, M.T., Uddin, M.S., Hossain, M.F., Abdulhakim, J.A., Alam, M.A., Ashraf, G.M., Bungau, S.G., Bin-Jumah, M.N., Abdel-Daim, M.M., and Aleya, L. 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