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We utilized docking algorithms to evaluate the interactions of these GL derivatives with key residues (His51, Asp75, Ser135, and Gly153) within 10 \u00c5 of the DENV-2 NS2B-NS3 protease binding pocket (PDB ID: 2FOM). It was found that compounds 11 and 17 exhibited unique binding patterns, forming hydrogen bonds with Asp75, Tyr150, and Gly153. Based on the molecular docking data, conjugates 11 with L-glutamic acid dimethyl ester, 17 with \u03b2-alanine ethyl ester, and 19 with aminoethantic acid methyl ester were further demonstrated as potent inhibitors of DENV-2 NS3 protease, with IC50 values below 1 \u03bcM, using NS3-mediated cleavage assay. Compound 11 was the most potent, with EC50 values of 0.034 \u03bcM for infectivity, 0.042 \u03bcM for virus yield, and a selective index over 2000, aligning with its strong NS3 protease inhibition. Compound 17 exhibited better NS3 protease inhibition than compound 19 but showed weaker effects on infectivity and virus yield. While all compounds strongly inhibited viral infectivity post-entry, compound 19 also blocked viral entry. This study provided valuable insights into the interactions between active GL derivatives and DENV-2 NS2B-NS3 protease, offering a comprehensive framework for identifying lead compounds for further drug optimization and design as NS2B-NS3 protease inhibitors against DENV.<\/jats:p>","DOI":"10.3390\/v16121926","type":"journal-article","created":{"date-parts":[[2024,12,17]],"date-time":"2024-12-17T03:46:02Z","timestamp":1734407162000},"page":"1926","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Discovery of Potent Dengue Virus NS2B-NS3 Protease Inhibitors Among Glycyrrhizic Acid Conjugates with Amino Acids and Dipeptides Esters"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1998-3310","authenticated-orcid":false,"given":"Yu-Feng","family":"Lin","sequence":"first","affiliation":[{"name":"Department of Medical Laboratory Science and Biotechnology, Asia University, Taichung 41354, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hsueh-Chou","family":"Lai","sequence":"additional","affiliation":[{"name":"Division of Hepato-Gastroenterology, Department of Internal Medicine, China Medical University Hospital, Taichung 404327, Taiwan"},{"name":"School of Chinese Medicine, China Medical University, Taichung 404328, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chen-Sheng","family":"Lin","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology, Kuang Tien General Hospital, Taichung 433401, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ping-Yi","family":"Hung","sequence":"additional","affiliation":[{"name":"Department of Medical Laboratory Science and Biotechnology, China Medical University, Taichung 404328, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ju-Ying","family":"Kan","sequence":"additional","affiliation":[{"name":"Department of Medical Laboratory Science and Biotechnology, China Medical University, Taichung 404328, Taiwan"},{"name":"The Ph.D. Program of Biotechnology and Biomedical Industry, China Medical University, Taichung 404328, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shih-Wen","family":"Chiu","sequence":"additional","affiliation":[{"name":"Institute of Bioinformatics and Systems Biology, National Yang Ming Chiao Tung University, Hsinchu 300093, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8363-6244","authenticated-orcid":false,"given":"Chih-Hao","family":"Lu","sequence":"additional","affiliation":[{"name":"Institute of Bioinformatics and Systems Biology, National Yang Ming Chiao Tung University, Hsinchu 300093, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1406-0293","authenticated-orcid":false,"given":"Svetlana F.","family":"Petrova","sequence":"additional","affiliation":[{"name":"Ufa Institute of Chemistry, Ufa Federal Research Centre of RAS, Ufa 450054, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6291-5260","authenticated-orcid":false,"given":"Lidia","family":"Baltina","sequence":"additional","affiliation":[{"name":"Ufa Institute of Chemistry, Ufa Federal Research Centre of RAS, Ufa 450054, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0165-2652","authenticated-orcid":false,"given":"Cheng-Wen","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Medical Laboratory Science and Biotechnology, Asia University, Taichung 41354, Taiwan"},{"name":"Department of Medical Laboratory Science and Biotechnology, China Medical University, Taichung 404328, Taiwan"},{"name":"The Ph.D. Program of Biotechnology and Biomedical Industry, China Medical University, Taichung 404328, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,12,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"268","DOI":"10.1016\/j.ijid.2020.02.018","article-title":"Discovery and development of safe-in-man broad-spectrum antiviral agents","volume":"93","author":"Andersen","year":"2020","journal-title":"Int. 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